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.

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.