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We investigated the mechanisms by which endogenous TNF-α modulates host defenses during experimental primary and secondary pulmonary infection with Histoplasma capsulatum (Hc). Neutralization of TNF-α in vivo resulted in increased CFU and 100% mortality in naive and immune mice challenged with Hc intranasally. Levels of IFN-γ and granulocyte macrophage-CSF were elevated in TNF-α-neutralized naive mice, whereas IL-4, -6, -10 and TGF-β did not differ from controls. In contrast, in secondary histoplasmosis, significant elevations of IL-4 and -10 were observed in TNF-α-depleted mice. Alveolar macrophages (Mφ) did not exert fungistatic activity against Hc after exposure to recombinant murine TNF-α, recombinant murine IFN-γ, or both. The increase in susceptibility to primary Hc infection was associated with diminished production of reactive nitrogen intermediates by alveolar Mφ from TNF-α-depleted mice, whereas production of nitric oxide during secondary histoplasmosis was similar in both groups. Upon secondary challenge, TNF-α-depleted mice were rescued by concomitant neutralization of IL-4 and IL-10, but not either cytokine alone. Thus, TNF-α is critical for controlling primary and secondary infection with Hc, and the mechanisms that lead mice to succumb to primary or secondary infection when endogenous TNF-α is blocked are different.