[5][6] In 1857, Abner Marsh, an unattractive but highly skilled Mississippi River captain, is grappling with a financial crisis when he is contacted by Joshua York, a rich, soft-spoken gentleman.

Abner's own suspicions begin to grow when he finds scrapbooks in Joshua's cabin containing newspaper clippings detailing many mysterious, unexplained deaths.

Abner confronts Joshua, who reveals that he and his friends are vampire hunters, using the Fevre Dream as their base of operations to investigate a trail of unusual deaths and disappearances along the river.

Eventually he finally reveals the whole truth: He and his friends are themselves vampires, humanoid beings specialized for and dependent upon hunting humans.

Abner later serves as an agent of the Underground Railroad and the United States Navy during the Civil War, all the while being haunted by the memory of his lost riverboat, which he retells to others as a ghost story.

The novel closes many decades later by suggesting that all vampires, though still effectively immortal, were eventually freed from their blood addiction by Joshua's potion and Abner's brave efforts on their behalf.

They make nighttime pilgrimages to Abner's grave overlooking the river, continuing to honor his heroic contribution to their cause of freedom, Joshua most often of all.