Tumor necrosis factor-a was detected in supernatants collected from BALB/cmouse peritoneal macrophages incubated continuously with Histoplasma capsulatum. The levels of TNFα measured by actinomycin D bioassay peaked within hours after exposure and then greatly declined by 24 h. TNFα was also measured in bronchoalveolar lavage fluid from BALB/cmice challenged intranasally with H. capsulatum. Lavage fluid TNFα levels exhibited the same pattern as the in vitro supernatants; they peaked within hours after challenge and lower levels were detected at 24 h. Treatment of mice with anti-TNFα antibody accelerated mortality in response to systemic infection and significantly increased tissue colony counts in the liver and spleen. In the murine model, TNFα is produced in response to H. capsulatum and appears to play some role in host defense to infection.