Roderick Blank (Simon Baker) is the 'annoyingly perfect and together' young man: in his 30s, he's got a great job (executive for 'Swallows', a fast-food restaurant chain designed to not look like a fast-food chain), a beautiful fiancee Fiona Wormwood (Julie Bowen) with whom he cannot wait to have a family, as well as demented best friends Zack (Neil Flynn) and Lester (Dash Mihok). On the day of his bachelor party, Roderick's assistant Trixie is relaying to him via cell-phone conversation his emails; when she opens the last one (sender unknown) it turns out to be a list of all the women Roderick has ever had a sexual relationship with and Roderick naturally assumes that since he's getting married, Fiona is the last woman on the list. Unfortunately for him, Fiona is only #29, the list keeps on going to 101.
Thinking it's a bachelor party joke from Lester, Roderick tries to blow it off, but just can't get it out of his mind: Who would know such intimate details about his life, and who could predict his future conquests, assuming the list was accurate? He looks at the 30th name - Carlotta Valdez - and wonders how and when this will occur. That night at his bachelor party, after the stripper 'Precious' mistakenly thinks he will have sex with her, even going so far as to unzip him and put on a condom he politely refuses her advances. However, a slip of the tongue (Precious thanks him by saying 'gracias') followed by a slip on the condom wrapper ends up put two and two together - the stripper, real name Carlotta Valdez - literally lands on him, and they have sex. But after learning of his subsequent infidelities, Fiona calls off the wedding.
Suddenly aware of his extremely good luck, Roderick proceeds to cross one name after another off of the list, including a tryst with a centrefold's leprosy-ridden grandmother, a Swallows drive-thru girl, a flight attendant, a reality-tv 'power lesbian' couple, and a self-help guru. The speed at which he is crossing names off of the list causes his friends to become concerned for his mental well-being; they convince him to bury the list. However after the end of a relationship with Lester's charming and quirky veterinarian (Leslie Bibb), Roderick digs up the list and returns to his old ways.
In the background of all this action is the activities of a woman nicknamed 'Death Nell' (Winona Ryder) in the press, a 'serial killer' of men who have committed sexual crimes: she seduces these men, and puts them into a permanent coma, leaving behind a line of feminist poetry in spray paint in the room. An agency which has been tracking death Nell's activities has also been keeping track of Roderick's, as it was them who sent the email to him in the first place. The email, as it turned out, came from a large quantum-mechanical computer called the 'Oracle' and the agency's job is to help those who receive emails keep from losing their minds.
Things begin to unravel for Roderick when he discovers that the identity of #101 Gillian de Raisx is in fact the notorious Death Nell and he begins to try everything in his power to avoid having sex and thus reaching the end of the list, including reading James Joyce's Ulysses, building scale models and taking up road biking. The last activity ends in disaster when he crashes his bike, and a school bus of female students from an all-girls Christian college 'help him' by helping themselves (believing that Roderick was sent by God to them) and proceed to use him to lose their virginities, thus catapulting him from #82-100 in the space of a single afternoon (and also causing Lester to write a letter to a men's magazine, presumably Penthouse Forum). When the agency tells him they are close to catching Death Nell, Roderick, guilt ridden over his treatment of his previous conquests, decides to go to the hotel where she will be staying and meet her face to face. Instead they meet in a diner and share a meal and conversation. Gillian/Nell reveals that she was a Poetry/Chemistry student who married young and was forced to perform many degrading sexual favours with her husband. After his death (caused by a broken neck after slipping on a pencil), Gillian realizes she inadvertently caused him to get his just rewards (she'd dropped the pencil accidentally after writing in her diary) and set out on her 'quest'. At the end of the meal, she tells Roderick she's exhausted from the whole ordeal and just wants to sleep. She shows him two purple pills and suggests they spend the night together, after which they would each take a pill and fall into a coma; Roderick agrees: they seduce each other, take the pill and fall into bed. On the wall behind them, in red spray paint is written 'The End'.
The next scene shows two bodies under a sheet in a bed, not moving. Suddenly a little boy of about three jumps onto the bed, awakening his parents: Roderick and Gillian. It is revealed that Gillian and Roderick never took the pills and have gotten married and now are the happy family that Roderick has always wanted to have. In a brief epilogue, Gillian's comatose victims are brought back to life.