In the opening scene, Fred Madison (Bill Pullman
), a saxophonist, is seen sitting in his house one morning, smoking a cigarette, looking disheveled when the intercom from the front door of his house buzzes. Over the intercom, a distorted man's voice says: "Dick Laurent is dead." When Fred looks out a window, police sirens are heard in the distance, but the streets outside his house are empty.
One evening, Fred's wife Renee (Patricia Arquette
) opts out of coming to the club to watch him and his band play; instead she plans to stay at home and read, an excuse Fred obviously finds flimsy. Red-faced and sweating, Fred plays discordant acid jazz at the Luna Club while the audience goes wild. He calls his house during a break, but Renee does not answer (several different phones at the house are seen to be ringing). Arriving home later, Fred sees Renee asleep in bed. Fred's expression shows his lingering doubts about Renee's faithfulness.
The next morning, a mysterious package arrives on the front doorstep containing a videotape. Renee doesn't mention the tape, but Fred sees it and demands that they watch it. The tape only displays a 20-second image of the outside of their home. The relieved Renee tells a perplexed Fred that the tape "might have been from a real estate agent."
One night Fred tries to make love to Renee, but gives up in failure, humiliated when she pats him on the back and dispassionately consoles him. He tells her about a dream he had: she was crying out for him, "Fred, where are you?" He couldn't find her and says that he saw someone in bed that looked like her but wasn't her. The Renee in the dream screams in terror as Fred approaches her in bed. Fred then seems to wake up in bed lying next to Renee, but when he turns to look at her, he sees not her face but the pale, frightening looking face of a man superimposed on her silhouette. Bill startles out of the nightmare, now fully awake for real.
As the days pass, a second tape arrives, showing the interior of their house-- the unseen intruder also films them in bed, sleeping. Fred and Renee call the police. Two detectives, Al and Ed (John Roselius and Louis Eppolito), watch the video. They recommend that Fred and Renee resume using their security system, and search the house for signs of forced entry. The departing cops say "We'll keep watch over the house. We'll do the best we can," having neither found nor resolved anything.
That evening, Fred and Renee go out to a party held by Andy (Michael Massee
) an old friend of Renee's. Renee drunkenly stumbles, giggling, into Andy's arms while pleading with Fred to get her another drink. A jealous Fred goes to the bar for a drink where he meets a strange-looking middle-aged man wearing all-black clothing, who is only known as the Mystery Man (Robert Blake
). The Mystery Man tells Fred that they've met before and that he is at his house right now. (Note: it was in fact the face of the Mystery Man that Fred saw in place of Renee's in his nightmare) Fred phones his house using the Mystery Man's cell phone and the voice of the Mystery Man answers at the house while he's standing right in front of Fred. After the Mystery Man walks away, the shaken Fred approaches Andy and asks him who the Mystery Man is and is told that he is a friend of Dick Laurent. When Fred repeats the message he heard on the intercom, that "Dick Laurent is dead," Andy nervously asks how Fred knows Dick Laurent and insists that "Dick can't be dead." Fred then forcibly grabs Renee and they leave the party.
Driving home, Fred questions Renee about Andy and her past connection to him. Renee answers vaguely, failing to alleviate Fred's jealous suspicions. Arriving back at their house, Fred makes Renee wait in the driveway while he checks inside for intruders and finds no one. While Renee prepares for bed and removes her makeup in the bathroom, Fred walks around the dimly lit house and finds himself standing in front of a dark hallway. Fred walks down the hallway and disappears, eventually encountering a mirror reflection of himself. Renee walks out of the bedroom and stands at the base of the hallway. She calls out for Fred, just as in his dream earlier. Shortly before Fred emerges from the darkness of the long hallway, we see a shadow moving through another part of the house.
The next morning, another tape arrives and Fred watches it alone. To his horror it contains gory images of him killing Renee. Time jumps abruptly and suddenly Fred is being beaten in an interrogation room by the same two police detectives, Al and Ed, who earlier offered to watch the house and now accuse him of killing his wife. A terrified Fred claims that he didn't kill Renee. But seconds later he becomes confused and pleads to the detectives, "Tell me I didn't kill her!"
Tried, found guilty and sentenced to death, Fred, still dazed and confused, is locked away on death row for the murder of Renee. Shortly after arriving, Fred is plagued by frequent headaches. After he collapses in the prison yard, he's brought into the infirmary where he complains to the prison doctor that he can't sleep. The doctor doses Fred with a sedative and he's locked back in his cell, where his headache continues to rage and he hallucinates strange visions of the Mystery Man, a burning cabin in the desert, and a dark stretch of highway.
The next morning, during a routine check of the cells, the prison guards are shocked to find that the man in Fred's cell is not Fred. The man is discovered to be Pete Dayton (Balthazar Getty
) a young, confused auto mechanic whom the prison officials discover has a past record for auto theft. Since Pete has committed no crime aside from the auto theft five years earlier, he is released into the care of his parents Bill and Candace (Gary Busey
and Lucy Butler
), who come to collect Pete dressed like bikers in black leather jackets, jeans and dark glasses. The Dayton family return home to their house in Van Nuys. At the same time, Pete is being followed by two detectives, named Hank and Lou (Carl Sundstrom and John Solari), to find out why and how Pete ended up in Fred Madison's prison cell.
Pete goes out that evening with his friends Steve V (Giovanni Ribisi
), Teddy, (Scott Coffey), Lanie (Heather Stephens) and Carl (Al Garrett) along with Pete's girlfriend Sheila (Natasha Gregson Wagner
). At a bowling alley with a bar in the back, they have drinks and dance. Sheila asks Pete about his whereabouts for the last several days, but Pete can't remember.
The next day, Pete returns to work at the garage where he is welcomed back by the owner Arnie (Richard Pryor
) and his co-workers including veteran mechanic Phil (Jack Nance
). Pete is called on by Mr. Eddy (Robert Loggia
), a charming but hot-tempered gangster, to tune up his Mercedes. Mr. Eddy takes Pete for a drive so that he can listen to the problem in the engine, which Pete fixes. During a drive, a pushy and belligerent motorist tailgates their vehicle, causing the gangster to erupt into a fit of road rage. Mr. Eddy chases down the tailgater and forces him off the road. Mr. Eddy and his two bodyguards drags the man out of his car where Mr. Eddy pistol whips him while berating him about road safety, a display of violence that shocks Pete. Mr. Eddy drops Pete back at the garage where he is spotted by the two detectives, Hank and Lou. Hank identifies Mr. Eddy as a certain criminal named Dick Laurent.
Hank and Lou follow Pete when he goes out that evening with Sheila. As the couple make out in Pete's car, she questions him on his moody behavior, but Pete maintains that he is just as confused as Sheila about recent events. They have sex in the front seat.
The next day, Mr. Eddy returns to the garage with his Cadillac for Pete to repair, accompanied by his beautiful blonde girlfriend, Alice Wakefield (also Patricia Arquette in a dual role). She and Pete make eye contact and we feel the chemistry ignite between these two characters. At the end of the day, Alice returns to the garage and invites Pete out for dinner. Against his better judgement, Pete begins a secret liaison with Alice, meeting her at the Starlite Motel. Hank and Lou continue to keep tabs on Pete, his affair with Alice giving them even more reason to connect him with Mr. Eddy / Dick Laurent and possible criminal activity.
As the days wear on, Pete begins to experience headaches and hallucinations similar to Fred's. When Alice phones Pete to cancel their nightly get-together, Pete instead rides his motorcycle to Sheila's house where he has rough sex with her, driven to satisfy passions awakened in him by the hot-blooded Alice.
One evening, Pete returns home to find his worried parents waiting to confront him about the night he vanished. Pete continues to claim that he has no memory about that night, except for flashes of being on the front lawn of his house with Sheila and his parents running after him. Bill and Candace indicate that they saw more but refuse to discuss whatever they saw with Pete.
The next day, Mr. Eddy pays Pete another visit at the garage where he brandishes a gun while making a veiled threat on Pete's life. He claims that he would kill anyone whom he caught fooling around with Alice.
After work, Pete secretly visits Alice at the Starlight. She tells him that Mr. Eddy suspects her and Pete of seeing each other. Alice reveals to Pete that Mr. Eddy is actually a porno producer named Dick Laurent. She tells Pete a story about how Mr. Eddy coerced her into a relationship with him by literally holding a gun to her head, but Pete remains unconvinced that Alice is only a reluctant partner in this relationship, insisting "you liked it, huh?" Alice presents Pete with a plan to steal money from a friend of hers so they can leave town. She tells Pete that on the following night, she will meet with Mr. Eddy's associate Andy (the same Andy who knew Renee in the first half of the story) at Andy's house. She'll facilitate Pete's entry into the house so that they can both rob Andy and use the money to run away together. Pete is wary of trusting Alice, but also overwhelmed by his desire to have her.
That same evening when Pete comes home, he is confronted by an enraged Sheila over his infidelity. She accuses him of being "different," and tries to persuade Bill and Candace to tell Pete the truth about "that night," but they remain close-lipped. As Sheila runs off into the night, the phone rings inside Pete's house. The caller is Mr. Eddy, who, along with his associate, the Mystery Man, threatens Pete again, this time more directly. Frightened, Pete calls Alice and agrees to help with her plan.
The next night, Pete sneaks out of his house and away from the two detectives in their squad car. He takes a local bus to Andy's house and enters through the back door that Alice has left unlocked. As planned, Alice sends Andy downstairs to fix her a drink and Pete knocks him unconscious. On a huge projection screen in the center of the living room, a porno of Alice having sex plays in a loop. Pete also sees a framed group photo of Andy, Mr. Eddy, Alice and Renee, and asks Alice whether the nearly identical women are both her. She simply points to the blonde woman and tells Pete that it's her, mentioning nothing about the dark-haired Renee. Andy comes to and attacks Pete. Pete pushes Andy off of him, throwing the man across the room where he impales his forehead on the corner of a glass coffee table, a freak accident that kills him instantly. Pete, now suffering a nosebleed, is horrified by the nasty turn of events, but Alice seems untroubled, coolly removing Andy's jewelry and gathering other valuables. Pete stumbles upstairs, hallucinating a motel where a nightmarish version of Alice taunts Pete while having sex with a faceless man.
Pete and Alice flee in Andy's red sports car. They arrive at a cabin in the desert seen in both Fred's and Pete's visions. This is where Alice plans to meet the "fence" who will give them cash for the stolen goods. Alice looks around but finds the cabin empty. While waiting for the arrival of the fence, Alice and Pete make love on the desert sand. In the throes of passion, Pete whispers to Alice over and over that he wants her. Alice finally replies coldly: "you'll never have me."
Alice gets up and walks away, stark nude, into the desert cabin, leaving Pete lying on the sand. The man who rises from the sand is not Pete.... but Fred Madison, who seems to have exchanged places with Pete once again. Fred puts his clothes on and searches the desert cabin. He sees no trace of Alice-- instead he meets the Mystery Man again, who angrily informs Fred that Alice's name is not Alice, it's Renee, and demands to know who Fred is. The Mystery Man then points a video camera at Fred and begins to film him, slowly coming closer and closer. Fred flees the menacing gaze of the man and the camera, running back to Andy's car and driving away just before the Mystery Man's outstretched arm reaches him.
Fred drives to the Lost Highway Motel, a nightmarish place in the middle of the desert, and sees Renee check into a room with Mr. Eddy / Dick Laurent. Fred enters the adjoining room and hears them having sex. A while later, Renee leaves Mr. Eddy and drives away. Fred then breaks into Mr. Eddy's room and grabs him. The Mystery Man watches from Fred's room as Fred forces Mr. Eddy into the trunk of the Mercedes and drives off.
Somewhere in the desert, Fred stops the car and gets out to open the trunk, at which point Mr. Eddy leaps out and attacks him. The Mystery Man suddenly appears and gives Fred a knife to slash Mr. Eddy's throat. In answer to Mr. Eddy's question "What do you guys want?" the Mystery Man produces a mini TV, the screen of which shows Renee and Mr. Eddy watching a snuff film while engaged in foreplay. The Mystery Man shoots Mr. Eddy to death and whispers something inaudible to Fred. The Mystery Man disappears and Fred (now holding the gun) drives off in Mr. Eddy's Mercedes, leaving Mr. Eddy's body in the desert wilderness.
Back at Andy's house, all four of the detectives, Al and Ed, Hank and Lou, investigate the crime scene. One of them notices the group photo of Renee, Mr. Eddy / Dick Laurent and Andy. Alice is no longer in the photo. The detectives identify the woman in the photo as Renee, "Fred Madison's wife" and note that the photo links her with Dick Laurent. However, the fingerprints all over the crime scene belong to Pete Dayton, now the prime suspect in Andy's murder. One of the detective's states: "You know what I think? I think there's no such thing as a bad coincidence."
In the final scene, things come full circle as Fred, still driving Mr. Eddy's Mercedes and wearing Pete's clothes, drives to his house where it's revealed that he is the person who left the cryptic message Fred heard through the intercom at the beginning of the movie: "Dick Laurent is dead." The two police detectives, Al and Ed, pull up in their squad car. Seeing the detectives advancing towards him, Fred runs back to his car and drives off with the detectives in hot pursuit. As darkness falls, Fred speeds down the desert highway with several police cars close behind. He screams as his head begins to shake and his features blur. The scream fades and we're left with the image from the opening credits, a dark, two-lane highway that rushes silently past with no surrounding landscape or apparent destination.