The ability of Pneumocystis carinii to induce tumor necrosis factor (TNF)-alpha release by monocytes/macrophages from immunocompetent humans was investigated. Monocytes and monocyte-derived macrophages from healthy individuals produced an increased amount of TNF-alpha when exposed to P. carinii cysts obtained from rats with steroid-induced pneumocystosis. The cysts induced increased TNF-alpha production in a dose-dependent manner; baseline TNF-alpha production was restored after addition of an anti-P. carinii hyperimmune serum. Kinetics experiments showed that the secretion of TNF-alpha occurs early and reaches a maximal peak after 8 h. Since TNF-alpha is directly lethal to P. carinii in vitro, it is suggested that the production of this cytokine in response to the cysts may be one of the mechanisms for the control of this parasitic infection.