The narrative follows Leon S. Kennedy fighting the mutated William Birkin for most of the story, while Claire Redfield fights the Tyrant. The book downplays most of the puzzle-solving elements from the game and focuses more on the interaction between the characters. There are also added scenes in the book involving the supporting characters such as Ada Wong, Annette Birkin, Sherry Birkin, and Police Chief Brian Irons. The ending is slightly altered, in which the survivors of S.T.A.R.S. Exeter, characters featured in Caliban Cove (including Rebecca Chambers, pick up Leon, Claire, and Sherry, as opposed to the "walk into the sunrise" ending featured in the game.
Due to City of the Dead being written before the release of Resident Evil 3: Nemesis the book has some contradictions. For example, in the beginning of the book, Jill Valentine leaves Raccoon with Chris Redfield and Barry Burton to infiltrate Umbrella's HQ in Europe. In the game series, however, Jill has to fight her way out of Raccoon, Chris has already skipped town, and Barry comes back to help Jill escape at the end. In the end, Sherry, Leon, and Claire ride away in a train.