Histoplasma capsulatum is a facultative intracellular fungus that spreads lymphohematogenously to involve organ systems rich in mononuclear phagocytes. We explored herein the in vivo effect of anti-CD8 rat mAb on the course of murine disseminated histoplasmosis. Treatment with anti-CD8 mAb caused a selective depletion of CD8+ T cells in naive mice infected with H. capsulatum. The loss of CD8+ T cells was associated with an increased number of H. capsulatum CFU in spleens and livers of mice during the first 3 wk of infection. Transgenic beta 2-microglobulin-deficient mice (beta 2 M-/-) that lack MHC class I Ag and CD8+ T cells or heterozygous littermates were injected with H. capsulatum. At wk 1 of infection, the number of CFU in livers and spleens of beta 2 M-/- mice was similar to that of littermates. At wk 2 and 3, however, the fungal burden in spleens and livers of beta 2 M-/- mice was larger than that of heterozygous littermates. H. capsulatum-immunized mice given anti-CD8 mAb manifested impaired clearance of H. capsulatum upon rechallenge with a large inoculum of yeasts when compared to immunized controls. Histopathologically, the inflammatory response in spleens and livers of CD8+ T cell-depleted mice was similar to that of mice given control Ab. The results indicate that CD8+ T cells are necessary for optimal clearance of the fungus from tissues of mice infected with H. capsulatum.