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.

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.

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.

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.

With Pam's body now rotting as the result of the witch's spell, Bill decides to take action and imprisons Marnie, who continues to have visions of an ancient spirit. He wants her to reverse the spell she's placed on Pam but she says she simply doesn't know how. Bill is none too pleased when he learns that Sookie is hiding Eric. Neither is Tara who refuses to believe that Eric has changed. Meanwhile, Jason is recovering and has an erotic dream involving Jessica. He also learns that a full moon is in the offing. Arlene and Terry decide they need an exorcism and seek some local help. Lafayette and Jesus head to Mexico to get some help of their own.

Now free, Sookie must decide between Eric and Bill. It's not an easy decision and she soon realizes that her turmoils are not yet over when someone comes gunning for her. Having taken over Lafayette's body, Marnie is intent on seeking revenge. She also wants additional powers however and knows exactly where to get them. Sookie has to save Bill and Eric from her but gets help from an unexpected source. Jason meanwhile decides it's time to tell Hoyt about sleeping with Jessica. Hoyt doesn't take it too well. Jason and Jessica however come to an understanding about their relationship. Andy Bellefleur tries to make amends about his recent strange behavior and Arlene gets a visit from the last person she wanted to see.

Sookie weighs a future with and without Bill. Eric and Pam struggle with their uncomfortable partnership with Mr. Gus. Sam makes a choice, while Andy comes upon an unexpected inheritance.