The film follows Dr. Hess Green (Duane Jones), a wealthy black anthropologist who is doing research on the Myrthians, an ancient African nation of blood drinkers. One night, while staying in Green's lavish mansion, richly decorated with African art, his unstable assistant George Meda (Bill Gunn) threatens suicide. Green successfully talks him down, but later that night Meda attacks and stabs Green with a Myrthian ceremonial dagger, and then kills himself. Green survives, but on discovering the body, drinks Meda's blood; he has become a vampire endowed with immortality and a need for fresh blood. He steals several bags of blood from a doctor's office, but finds that he needs fresh victims.
Soon, Meda's estranged wife, Ganja Meda (Marlene Clark), arrives at Green's house searching for her husband. Green and Meda quickly become lovers, and she moves into Green's mansion. When she unwittingly discovers her husband's corpse frozen in Green's wine cellar she is initially upset, but then agrees to marry her host, who turns her into a vampire as well. Ganja is initially horrified by her new existence, but Green teaches her how to survive. Soon he brings home a young man whom Ganja seduces and then kills. The two vampires dispose of the body in the water.
Eventually, Green becomes disillusioned with this life and resolves to return to the Christian church headed by his chauffeur, Reverend Luther Williams (Sam Waymon). Returning home, he kills himself by standing in front of a cross. Ganja, though saddened by his death, lives on, presumably continuing her vampiric lifestyle. The film ends with the young man Ganja had earlier killed rising out of the water, naked but alive, and running toward her.
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