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The supernatural thriller takes place on Halloween in 1969, following 21-year-old New England college student Alan Parker (Jonathan Jackson). Distraught that his girlfriend (Erika Christensen) has broken up with him, he attempts suicide but fails and then learns that his beloved mother (Barbara Hershey) has had a stroke. Hitchhiking through rural Maine to visit her bedside, the young man is picked up by a mysterious driver (David Arquette) who carries his own haunting secrets.
Julian and the few friends who managed to escape from Necropolis are all now in college and putting their Hybratech experiences behind them. But that doesn't last as accidentally Julian and Jenny discover a sinister chemical canister hidden away in a secret room. Trying to dissect this chemical, labeled as Trioxyin-5, they leave it with their friend Cody for analysis. Unfortunately, Cody quickly sees the potential to create a new party drug out of it and make himself some easy money. He lies to Julian and produces a huge batch of 'Z' that he sells across the college campus. As the drug becomes more and more popular and Halloween approaches, practically everyone in the college has taken a little 'Z'. As hundreds of innocent college students become brain hungry zombies, holiday costumes make it difficult to tell who is still alive and who is one of the living dead!