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Having experienced the trauma of the first two pictures, Campbell's Sydney Prescott now lives in a secluded area of California where she works as a rape crisis counselor from her home. Her whereabouts are unknown even to her surviving friends (save for Dewey, played by Arquette.) Gale Weathers (Cox) has become a hugely successful news reporter (of a sensationalist style) thanks to the books she wrote revolving around the murders of the first two films (and subsequent films based on the books.)
The film begins when Cotton Weary (Liev Schrieber), the man long-ago suspected of killing Sydney's mother, is slaughtered (along with his girlfriend). Suspected of being related to the original killings, Los Angeles police (including Mark Kincaid, played by Patrick Dempsey) want to contact Sydney to question her. It seems a photograph of Maureen Prescott, Sydney's mother, was left at the murder scene.
Meanwhile Gale Weathers visits the set of the latest film in the "Stab" series, "Stab 3: Return to Woodsboro." There she discovers a set that looks identical to the scene of the horrific 'real' events that plagued her in the first "Scream." She also meets the various performers portraying the real people she knew or knows: Angelina Tyler (Emily Mortimer) as "Sydney"; Sarah Darling (Jenny McCarthy) as "Tatum"; and Tom Prinze (Matt Keeslar) as "Billy".