The mechanisms responsible for aberrant immune function associated with chronic ethanol use remain obscure, but a decrease in monocyte numbers is often reported for individuals who chronically abuse ethanol. We investigated, using human HL-60 promyelocytic cell line, the possibility that ethanol induces apoptosis which contributes to decreased monocyte numbers. Characteristic features of apoptosis were observed 4 days after ethanol treatment, as documented by increased DNA fragmentation; enhanced expression of phosphatidylserine, an early marker of apoptosis; and the appearance of a hypodiploid apoptotic cell population identified by flow cytometry analysis of the cell cycle. Treatment with the protein kinase C inhibitor, GF 109203X, potentiated ethanol-induced apoptosis. Direct induction of human HL-60 cell apoptosis by ethanol and potentiation of ethanol-induced apoptosis by inhibiting protein kinase C provides a partial explanation for the cytotoxic effects of ethanol on hematopoietic progenitor cells and establishes a link between inhibiting protein kinase C activity and ethanol-induced apoptosis.