We determined whether the absence of IL-10 in mice influenced protective and memory immunity to Histoplasma capsulatum. IL-10−/− mice cleared primary and secondary infection more rapidly than wild-type controls. Administration of mAb to TNF-α or IFN-γ, but not GM-CSF, abrogated protection in naive IL-10−/− mice; mAb toTNF-α, but not IFN-γ or GM-CSF, subverted protective immunity in secondary histoplasmosis. The inflammatory cell composition in IL-10−/− mice was altered in those given mAb to IFN-γ or TNF-α. More Gr-1+ and Mac-3+ cells were present in lungs of IL-10−/− mice given mAb to IFN-γ, and treatment with mAb to TNF-α sharply reduced the number of CD8+ cells in lungs of IL-10−/− mice. We ascertained whether the lack of IL-10 modulated memory T cell generation or the protective function of cells. The percentage of CD3+, CD44 high, CD62 low, and IFN-γ+ cells in IL-10−/− mice was higher than that of wild-type at day 7 but not day 21 or 49 after immunization. Fewer splenocytes from immunized IL-10−/− mice were required to mediate protection upon adoptive transfer into infected TCR αβ−/− mice. Hence, deficiency of IL-10 confers a salutary effect on the course of histoplasmosis, and the beneficial effects of IL-10 deficiency require endogenous TNF-α and/or IFN-γ. Memory cell generation was transiently increased in IL-10−/− mice, but the protective function conferred by cells from these mice following immunization is strikingly more vigorous than that of wild-type.