The cynical and skeptical writer Mike Enslin writes books evaluating supernatural phenomena in hotels, graveyards and other haunted places, usually debunking the mystery. While writing his last book, he travels from Los Angeles to New York to spend one night in the evil room 1408 of the Dolphin Hotel, which is permanently unavailable for guests. The reluctant manager Mr. Gerald Olin objects to his request and offers an upgrade, expensive booze and finally the reports relating the death of more than fifty guests along decades in the cursed room. However, Mike threatens Mr. Oiln, promising to sue the hotel, and finally checks in the room. Along the night, he finds that guests of room 1408 can check out when they like, but they can never leave the room alive. 

Black marketers loot an abandoned Soviet bio-weapons lab in Siberia, releasing a weaponized strain of Small Pox which quickly turns into a global pandemic. The remaining 2%, who survive the 98% mortality rate suffer varying degrees of blindness, physical deformation, sterility and madness. Without any food source coming into the cities, what food stocks have not already been looted have been horded. With starvation threatening the plague survivors, they turn to cannibalism, preying upon each other. The unscarred Lionel Verney, by default, becomes the strongest man standing, competing for his existence against entire clans of diseased survivors among the ruins of what once was the 21st century.