Exposure to hypoxia (PO₂ = 9 ± 1 torr) increased human peripheral blood mononuclear cell production and secretion of interleukin-1 (IL-1)α, IL-1β, and tumor necrosis factor (TNF) (percent of control = 190% for IL-1α, p = 0.014; 219% for IL-1β, p = 0.014; and 243% for TNF, p = 0.037) following treatment with endotoxin (1 ng/ml). Hypoxia potentiated the increased production of these inflammatory cytokines at subthreshold levels of endotoxin with potentiation increasing at lower O₂ concentrations. Hypoxia also increased cytokine production induced by the tumor promoter phorbol myristate acetate, suggesting a generalized biologic response. We conclude that hypoxia increases IL-1 and TNF production and speculate that this mechanism aggravates a variety of pathologic conditions involving endotoxin such as adult respiratory distress syndrome (ARDS), multiple organ failure, and septic shock.