The film follows a man, Jack (Jesse Metcalfe), faking insanity in order to save his sister, Lily (Kiele Sanchez), who has been involuntarily institutionalized. The siblings soon find that the strange doctor at the asylum, Mr. Gianetti (Peter Stormare), has been testing an experimental compound, orphium, on the patients that seems to be turning them into flesh-eating zombies; Loomis (Kurt Caceres), another patient, spreads the infection. The two siblings band together with a terminally paranoid man, Dave (Kevin Sussman), and a helpful nurse, Nancy (Olivia Munn), in the hopes of finding a way out of the asylum. They are attacked by most of the prisoners and staff, who kill Nancy; while on the 4th floor, they encounter the doctor, who gives Dave an icepick lobotomy, incapacitating him; he attempts to get Jack too, but ends up being infected by Loomis. At the end of the film, as the two siblings are in a police car heading to the asylum to investigate, the officers (Mark Kelly & Sharon Schaffer) accidentally let the patients escape into the outside world. It ends with a panning shot, revealing the city below the asylum's hillside location. The secondary plot focuses on the affair between Charles (Evan Parke) and Heather (Lisa Athrowe).

Kathryn Merte (Amy Adams) is the manipulative, cold-hearted daughter of social climber Tiffany Merte-Valmont (Mimi Rogers). Tiffany has just married again, and Kathryn is not getting along well with her new stepbrother Sebastian (Robin Dunne), who is just as skilled in the venomous art of social gamesmanship as Kathryn. Together they negotiate the tricky paths of sexual and personal power at their upscale private high school.