In 2019, a pandemic disease has turned most of the world’s population into vampires. As human numbers dwindle, the need for blood becomes desperate. When deprived of blood for extended periods, vampires degenerate into subsiders, aggressive bat-like creatures. Humans are captured and harvested in laboratory farms while scientists research a synthetic blood substitute. The main supplier of blood in the United States is the pharmaceutical company Bromley Marks, run by Charles Bromley (Sam Neill). Edward Dalton (Ethan Hawke) and Chris Caruso (Vince Colosimo) are hematologists working on the blood substitute. Under pressure from Charles, they try multiple versions in a series of failing clinical trials. Edward secretly refuses to drink human blood and faces a strained relationship with his brother, Frankie (Michael Dorman), a human-hunting soldier.
A covert group of humans led by Audrey (Claudia Karvan) rescues and hides humans from vampire patrols while they attempt to win allies amongst the vampires. Audrey contacts Edward because of his human sympathies and scientific specialty. He meets Elvis (Willem Dafoe), a man cured of vampirism by brief exposure to sunlight. After some experimentation, Edward is able to duplicate this effect and is cured himself.