The concerted action of several cytokines is necessary for resolution of both primary and secondary infection with Histoplasma capsulatum. Among the soluble factors that contribute to tissue sterilization, TNF-α stands as a central mediator of protective immunity to this fungus. In this study, we explored the regulation of protective immunity by TNFR1 and-2. In primary pulmonary infection, both TNFR1−/− and-2−/− mice manifested a high mortality after infection with H. capsulatum, although TNFR1−/− mice were more susceptible than TNFR2−/− mice. Overwhelming infection in the former was associated with a pronounced decrement in the number of inflammatory cells in the lungs and elevated IFN-γ and TNF-α levels in the lungs. In contrast, IFN-γ levels were markedly decreased in TNFR2−/− mice, and treatment with this cytokine restored protective immunity. Lung macrophages from both groups of knockout mice released substantial amounts of NO. Upon secondary infection, TNFR2−/− mice survived rechallenge and cleared infection as efficiently as C57BL/6 animals. In contrast, mice given mAb to TNFR1 succumbed to reexposure, and the high mortality was accompanied by a significant increase in fungal burden in the lungs. Both IL-4 and IL-10 were elevated in the lungs of these mice. The results demonstrate the pivotal influence of TNFR1 and-2 in controlling primary infection and highlight the differences between these receptors for regulation reexposure histoplasmosis.