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In a society where humans and vampires co-exist, set in the small town of Bon Temps, Louisiana, Sookie Stackhouse is a young woman who may have found a perfect boyfriend. Sookie is clairvoyant and constantly hears people's thoughts so it makes dating a bit difficult since she tries to keep her ability a secret. When 173-year-old vampire Bill Compton walks into the Merlotte's Bar and Grill where she works as a waitress, she realizes that she can't "hear" what he's thinking, thus giving away his origins since she can't hear the thoughts of those whom are technically dead. Vampires "came out of the coffin" two years ago when the Japanese invented Tru Blood, a synthetic blood substitute. Sookie rescues Bill when a couple of lowlife rednecks, the Rattrays, try to steal his blood to sell on the black market, but she may have a price to pay for interfering. Meanwhile, Sookie's older brother, Jason, is a smooth-talking hustler and lothario who works part-time with a construction crew, and who gets arrested after a local woman that he had a one-night stand with is found strangled. Tara Thornton is Sookie's ill-tempered best friend whom finds her bad-boy brother irresistible. Sam Merlotte is the owner of Merlotte's Bar, who keeps his romantic feelings for Sookie to himself. Lafayette Reynolds is Tara's flamboyant gay cousin and the short-order cook at Merlotte's as well as Jason's co-worker at his construction day job who has more to offer than his gourmet foods. Arlene Fowler is a middle-aged divorcée and another of Sookie's friends and co-workers at Merlotte's looking for a new husband to help raise her two children. Andy Bellefleur is the local police detective working with the collaboration of the town sheriff, Bud Dearborn, who thinks the town may have a killer in their midst as they investigate the strangulation case.

Mack and Denise Rattray get their revenge on Sookie but Bill steps in to save her. Subsequently, Sookie's senses begin to undergo a transformation. She later learns that the Rattrays are dead and the police immediately suspect Bill. She also begins to wonder just how far vampires will go when a leading opponent of the Vampire Rights Act is killed in an accident. Bill agrees to visit Sookie and her grandmother and Tara and Jason invite themselves for the evening. Jason Stackhouse gets to see the video of his evening with Maudette Pickens. The police release him but his experience doesn't dissuade him from sleeping with every woman who will have him.

Bill Compton's allure is diminished somewhat when Sookie visits him in his home and finds that several other rather nasty vampires has also dropped in for a visit. Bill protects her from his one-time friends but she sees a nasty side of vampire life. Dawn Green spends the night with Sookie's brother Jason but she kicks him out after an argument. She is found strangled later that day. Tara walks out on her alcoholic mother and spends the night with her employer, bar owner Sam Merlotte.

With the town's second murder in a week, Jason is again the number one suspect, but Tara provides him with an alibi. Knowing that both Maudette and Dawn had frequented the Fangtasia vampire club, Sookie asks Bill to take her there as she tries to find evidence that will clear her brother. Both of the dead girls were well known at the club and Sookie meets Eric, the vampire elder. Sam Merlotte seems to have a few eccentricities of his own. Jason buys vampire blood - an aphrodisiac - from Tara's cousin Lafayette and despite clear instructions to never take more than one or two drop at any one time, downs the entire vial with somewhat painful results.

After their encounter with the racist policeman, Sookie tells Bill that she won't be seeing him anymore. The next day, Bill keeps his promise to Sookie's grandmother, Adele 'Gran' Stackhouse, to speak at the monthly meeting of the Descendents of the Glorious Dead. Bill becomes very popular when he reminiscences about the Civil War and the Mayor gives him an old photo he found in the archives. Bill also recalls the circumstances of how he became a vampire. Meanwhile, Sam asks Sookie out on a date, but things don't go as he planned for she tells him that she is not ready to commit. A little later, Sookie is shocked by what she finds when she gets home. Elsewhere, Jason gets more vampire blood from Lafayette, and he also takes an interest in Tara after he hears she has a thing for him. But Jason instead sets his sights on a local woman, named Randi Sue, as his latest sexual conquest.

Sookie must deal with her emotions when her grandmother is the mysterious serial killer's latest victim. She can't block out the thoughts of others and she knows many of the townspeople think the main reason her grandmother is now dead is her association with a vampire. She has a very clear message for them at the woman's funeral. Despite Sam and Bill's pleading, Sookie insists on staying in the house, but she does decide to spend the night with Bill to lose her virginity once and for all. Meanwhile, Jason wrestles with withdrawal symptoms from his 'V Juice' habit, which leads him to lash out at Sookie when he hears about Gram Adele's murder, and he also punches Detective Andy. Also, Tara has a run-in with her drunken mother Lettie Mae at Adele's funeral, who tells her some unsettling facts about herself. Tara then asks Sam to have sex with her at her motel room to look for "something right" between them, while Jason has his night with Randi Sue, and Sookie finally gives in to her carnal desires with Bill.

After spending the night with Bill, Sookie is convinced that she has found the man of her dreams as the person who took her virginity. But Sookie's fellow workers and the customers at the bar don't quite agree as rumors spread of her relationship with a vampire. Sookie's painful childhood revelation about her Uncle Bartlett spurs Bill into action. Meanwhile, Tara's alcoholic mother, Lettie Mae, is convinced that she needs an exorcism and when Tara refuses to pay, she tries to get a loan from the bank. Jason is desperate to get more vampire blood and visits Fangtasia where he meets a young woman, named Amy, who introduces himself to something altogether different. Sam Merlotte is seen by Andy and a few others running across the bayou... naked. The patrons at the bar are not too pleased when a group of Bill's one-time vampire friends, Malcolm, Liam, and Diane, show up. When they mention that they've bought a house locally, three of the redneck good old boys decide to do something about it.

Sookie prepares for the worst. Tara struggles with her mother's miraculous recovery. Amy ropes Jason into a dark game. Eric summons Sookie for a task she is uniquely qualified for.

When Sookie finds Sam asleep without clothes at her bed, he reveals his own secret to her that he happens to be a shape shifter, plus his pet dog seen around the bar is really him in disguise. Sam also recalls important events in his life. Arlene and Rene have their engagement party at Sam's bar and Sookie, already freaked out by Sam's revelation, is attacked by an unseen person in the darkened kitchen. Meanwhile, Tara decides to undergo the exorcism, but later discovers something about the exorcist Miss Jeanette. Jason decides it's time to do something about the captive Eddie, while Amy thinks differently. Elsewhere, Bill has to face the music and appears before a vampire tribunal over his self-defense killing of Longshadow. The normal sentence would be to spend five years in a silver-wrapped coffin but the Magister has a better idea... to make Bill turn a human into a vampire.

Jason and Amy have to clean up after Eddie's demise but it pushes Jason to the edge and he isn't sure if he wants to continue his relationship with her. Meanwhile, Sookie caught a glimpse of something during her encounter with the serial killer and she and Sam travel to a diner in an adjoining county to see if they can get more information. What they learn is that the killer may once have struck there as well. Elsewhere, Bill completes the tribune's sentence by turning Jessica into a vampire, but when he tells her what has happened, he doesn't quite get the reaction he was expecting. Tara is arrested for drunk driving and her mother refuses to bail her out. A stranger, named Maryann Forrester, comes to her rescue. Also, the unseen serial killer strikes again by killing Amy and the police arrest Jason after the killer frames him.

Sookie comes face-to-face with the killer as Jason's fate is up in the air. The town of Bon Temps learns a horrifying secret about a resident.

After Sookie identifies the vampire bartender Longshadow responsible for stealing from Fangtasia, Bill steps in to protect her. In doing so however, he breaks a vampire taboo and must now face the consequences from Eric and his clan for killing one of their own. Knowing he will be away, he asks Sam Merlotte to keep an eye on Sookie. Meanwhile, Jason and Amy take their vampire captive, Eddie, to Jason's house and confine him to the basement. They draw his blood and Jason undergoes an odd transformation. With Amy now working at Merlotte's, Jason spends his spare time just talking to Eddie and they develop a rapport. Elsewhere, Tara visits her mother's exorcist, but decides she can't afford the $800 cost for her own exorcism. Sam agrees to lend Tara the money needed, while he also deals with Detective Andy Bellefleur who becomes suspicious about his past. With Bill away, Sookie chooses to spend the night at Bill's house but wakes up the next morning with a naked man on her bed...

A murder outside Merlotte's leaves everyone reeling.

Sookie babysits Jessica, but things take a difficult turn when Jessica is adamant about confronting her family. Jason makes an impression on Sarah and Steve.

Bill, Sookie, and Jessica travel to Dallas to carry out Eric's mission, while Maryann throws Tara a party for her birthday.

Bill and Eric rush to save Sookie after she is attacked by a mysterious creature.

Sookie and Sam each connect with one of their own; Jason is rewarded at the Light of Day boot camp; Eric reveals his past.

Sookie and Hugo embark on a dangerous mission to infiltrate the Light of Day and locate Godric.

Sam finds himself in a predicament; Sookie uses her telepathic powers to reach out to Bill; Lorena exercises her hold over Bill as his maker; Jason looks to sever his ties with the church.

Sookie's captivity takes an unexpected turn.

Vampires and humans clean up in the aftermath of the explosion. Eric tricks Sookie into drinking some of his blood, much to Bill's dismay. As a result of the lapse in security, Godric's leadership falls under review but his response surprises everyone, especially Eric, who begs him not to go through with his plan. In Bon Temps, Maryann is out to find Sam Merlotte and complete the ritual sacrifice. She casts a spell on everyone in Sam's bar to get them to look for him. Lafayette and Tara's mother forcibly remove her from Sookie's house. Hoyt and Jessica get used to their situation and Hoyt decides it's time to introduce his true love to his vampire-hating mother.

Sookie, Bill and Jason return to a Bon Temps turned upside down by Maryann.

Bill visits the vampire Queen of Louisiana to see what he can learn about Maryann and how they might be able to defeat her. The Queen isn't too preoccupied with Bill's requirements but does eventually tell him what has to be done. Back in Bon Temps, those who are not under Maryann's control plan their next moves. Sam Merlotte decides they need help and visits Eric who reluctantly agrees to see what he can do. Sookie and Lafayette have to try and rescue Tara yet again after she escapes and returns to Sookie's house in an attempt to save Eggs. Hoyt storms out of Bill's house after he and Jessica have a big fight over his mother. His mother reveals a few truths about his father.

The mayhem in Bon Temps reaches a fever pitch as Maryann prepares for her ultimate bestial sacrifice, conscripting Sookie to be Maid of Honor at the bloody nuptials. Meanwhile, Sophie-Anne warns Eric to keep the lid on Bill's inquisitiveness; Jason leads Andy into the heroic abyss; and Hoyt has a hard time swallowing Maxine's endless stream of insults. Deliberating on what may be his final move to save Sookie and the town, Sam is forced to put his trust, and his life, in a most unlikely ally.

Sookie and Jessica attempt to locate a kidnapped Bill, leading to a shocking revelation.