A son of Texas, Ron Woodroof (Matthew McConaughey) is an electrician and rodeo cowboy. In 1985, he is well into an unexamined existence with a devil-may-care lifestyle. He gets rodeo-goers so pissed off that he has to run away from them. The presence of a cop (Steve Zahn) who pretends to arrest him is what saves him. He is knocked out by electricity when trying to save a Latin illegal worker who got his leg caught up in a machine. Through all these experiences, Woodrooff continuously coughs a lot. After being knocked out, he wakes up at hospital, and doctor Vass (Griffin Dunne) and Dr. Eve Saks (Jennifer Garner) tell him that his inmunitary defenses are so low that it's a miracle he's still alive. Suddenly, Ron is blindsided by being diagnosed as H.I.V.-positive and given 30 days to live. Yet he will not, and does not, accept a death sentence.
After receiving the news, he participates in an orgy, like those he used to like so much. He also takes drugs, but he looks at a calender and feels down. His crash course of research reveals a lack of approved treatments and medications in the U.S., so Ron crosses the border into Mexico. There, he learns about alternative treatments and begins smuggling them into the U.S., challenging the medical and scientific community including his concerned physician, Dr. Saks. She notices the gold watch on the speaker who talks about the virus and the medicines. She is being told that, after all, medicine is a business. Meanwhile, Ron goes to the library and checks medicine literature on the subject, coughing all the time. He remembers the time when he probably caught it.
Ron goes to hospital again and Eve tries to help him because he is giving a hard time to nurse Frazin (Donna Duplantier), but Ron is an ass to her, shouting that he doesn't need a nurse but a doctor. Eve Saks helps him as much as he can anyway; she tells him that the medicines he heard on the TIME magazine in Germany are not available in the USA. She sends him to a support group, but he doesn't want to be seen with "faggots".
His own friends don't even want to sit near him anymore, and a bar brawl almost ensues. The first time he goes to the support group, he just takes leaflets about the matter and threatens one of the members of the audience who tried to hug him. When he goes to the oil field, his boss in line and the rest of the workers want him out of there, so he doesn't even get out of his car. A Hispanic orderly (Ian Casselberry) steals the drugs and sells them to him. Ron passes out.
An outsider to the gay community, Ron finds an unlikely ally in fellow AIDS patient Rayon (Jared Leto), a transsexual who shares Ron's lust for life. They share the same hospital room and Saks is both their doctor. On the 29th day, Ron looks like crap, but not necessarily like somebody who is about to die - he picks up a gun and thinks of committing suicide but cries and doesn't give in.
On 30th day, he reaches Mexico. Dr Sevard (Denis O'Hare) speaks to him. Ron pulls down his hospital dress in fear any gay man looks at him.
Rayon also shares Ron's entrepreneurial spirit: seeking to avoid government sanctions against selling non-approved medicines and supplements, they establish a buyers club, where H.I.V.-positive people pay monthly dues for access to the newly acquired supplies. Deep in the heart of Texas, Ron's pioneering underground collective beats loud and strong. With a growing community of friends and clients, Ron fights for dignity, education, and acceptance. In the years following his diagnosis, the embattled Lone Star loner lives life to the fullest like never before. The Mexican doctor who gives him proteins and DDC, which may help him, has lost his license in the USA; as those drugs have not been approved by American doctors, so he isn't supposed to take them with him.
Ron tries to smuggle them by he is caught by a border agent (Sean Boyd). Ron disguises himself as a priest and says that he is taking vitamins, not medicines. He sells the medicines on the streets. The drugs take a lot of time to be approved, so meanwhile, USA's doctors are prescribing medicines which can be considered poisons.
Rayon wants to buy a cocktail of drugs from him, but finally relents because she says that Ron doesn't deserve that money, as he is a homophobic ass. Ron drives after Rayon and sells her the drugs. Rayon suggests Ron to sell the cocktail within a gay bar. At first, nobody pays attention to him, and Rayon tells him to smile, so he makes his first sale there.
Soon Ron and Rayon strike up a partnership and they start selling admittance to a buyers' club, not anymore selling the drugs anymore. Dr Saks is worried about Rayon, who has just disappeared and changed address without telling her. They were on such friendly terms that Eve was even questioned about Rayon's fashion and dresses choices. She is appalled when Ron's address comes out as Rayon's new address.
Eve visits Rom's apartment and she is appalled that he is giving treatment to so many people. Ron has even began to care about Rayon's health and eating habits. At the supermarket, Ron comes across T. J. (Kevin Rankin) and introduces him to Rayon. Ron has to force him to shake hands with Rayon.
The queue of sick people is visible from the road. Not everybody can pay the 400 dollar membership fee anyway. Ron doesn't want Rayon to sell when high. She is a bit unpredictable because of her addiction to cocaine.
He travels to Japan to talk to Dr Hiroshi (Joji Yoshida), who tells him that he was not aware of the regulations against exporting drugs. Mr Yamata (Scott Takeda) who would sell the drugs under the counter. At the airport, he is about to inject himself but passes off. His cop friend learns that Ron has AIDS.
The doctor tells him to stop selling unknown drugs which have provoked a heart attack to him. An FDA Customs agent (Carl Palmer) tells him that he'll bust him if he can. Saks has even referred some of his patients to Ron.
Ron makes love to somebody while everybody is waiting up. Rayon's addiction increases. A news Anchor (Rachel Wulff) talks about demonstrations demanding medicines to be approved sooner. The FDA confiscates many drugs present at Ron's apartment, but they let him go with only a fine. Ron tells Rayon to stop shooting up or it will kill her.
Eve and Ron have a date and they talk about their pasts. Frank Young (Himself) appears to TV to address the problem but he doesn't say anything important and even Rayon dismisses his words. Rayon is extremely thin; she starts coughing and a friend of hers (Sunny, played by Bradford Cox)) takes him to hospital. Eve Saks sees her on hospital with nurse Frazin. Eve holds Rayon's hand, while Ron fakes Eve's signature on prescriptions. Nurse Frazin calls security when Ron storms in Rayon's hospital room and threatens his doctor - Rayon's dead.
Ron calls in a stripper (Neeona Neal). Both Ron and Eve are very affected by Rayon's death. The FDA keeps on putting pressure on him taking away his drugs. He goes to a conference by the FDA, which will allow him to use drugs for personal use, something which is considered a success.
Ron dies in 1992, 7 years after he was first diagnosed.