Sookie Stackhouse, a waitress with telepathic abilities, falls under the spell of a 173-year-old vampire; Sookie's brother finds himself in hot water.

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.

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.