There are many differences between Stephen King's book and the script for this film, many of them caused by the need to shorten the plot enough to facilitate a three-hour movie.
The most noticeable difference in the film is that the lead vampire, Barlow, is here portrayed as a blue-skinned monster instead of a suave European, as he is in the book. Barlow has no speaking lines in the film, and his appearance is so hideous that he looks inhuman (his look is clearly inspired by that of Max Schreck in the original "Nosferatu"). The novel has a completely different approach, modeling Barlow on Dracula; as he feeds on the blood of the characters, he seems to get younger and younger. He also is very seductive, and has a number of dialogue exchanges with the other characters.
There is also a plot device in the film where a brief opening scene establishes Mark and Ben in Guatemala, on the run from something. The scene is repeated at the conclusion of the film, this time showing us the outcome: they are apparently running from vengeful vampires from Salem's Lot, who have been relentelssly pursuing them across the world and have found them again. In the novel, there was no real reason for the vampires to go after Mark and Ben; instead, the two of them willingly left Salem's Lot behind because they couldn't deal with the task of clearing the town of the undead.
Several characters and subplots in the novel have been combined. The subplot involving Cully Sawyer catching his wife Bonnie having an affair has been changed; she is now Larry Crockett's secretary, and she is having the affair with Crockett himself. Likewise, there was a character in the novel named Jimmy, a doctor who became one of the vampire hunters alongside Ben and Mark. In the film, the character has been combined with that of Bill Norton, Susan's father. Finally, Matt Burke's name has been changed to Jason.
The dynamic of Ben and Mark Petrie's relationship is deeper in the book. They grow very close, father and son like, and at one point Ben tells Mark he loves him. In the film, their bond is merely by process of elimination. They just happened to be the two strongest survivors, and there is never any sense of emotional attachment. Also about Mark, although he still comes off inwardly witty, he doesn't say anything really clever in the film. The director forces his importance in the story with screen time. In the book, he delivers the sharpest dialogue in the story, making his character memorable without necessarily being ever-present.
The fate of Susan is another major difference. In the film, we never see what happened to her until the post script showing Mark and Ben in Guatemala, when she appears to them as a vampire.[/spoiler] In the novel, she is vampirized and left behind in the basement of the Marsten House for Ben and the others to find when they are looking for Barlow. Instead they find Susan, and Ben must then set her free by driving a stake through her heart.
The climactic scene is different in the novel. The book has Barlow moving one step ahead of the vampire hunters; he anticipates them coming for him in the Marsten House, so he changes the location of his coffin to that of the root cellar in Eva Miller's boarding house. In the film, Barlow never relocates his coffin, and the confrontation takes place in the basement of the Marsten House.