The course of experimental systemic Coccidioides immitis infection was assessed quantitatively and histologically in beige mice, congenitally athymic nude mice, and their respective normal counterparts. After intravenous inoculation with 50 arthroconidia, the number of viable C. immitis cultured from the spleens, livers, and lungs progressively increased throughout the assay in the organs of all mice. During the first 2 weeks of infection, significantly greater numbers of CFU were recovered from the spleens and livers, but not the lungs, of nude mice than from the respective organs of their phenotypically normal littermates. Significantly greater numbers of CFU were cultured from the lungs and spleens of beige mice compared with the number recovered from their functionally normal littermates. After intranasal inoculation, extrapulmonary dissemination of C. immitis occurred at an equal rate and resulted in similar organ burdens in nude mice and their normal littermates. Histological examination of infected tissues revealed a characteristic mixed inflammatory cell infiltrate in euthymic mice; the response in nude mice was less severe, consisting predominantly, if not solely, of granulocytes. In addition, in tissue sections from nude mice, but not in those from their euthymic counterparts, mature spherules were frequently observed to be devoid of an associated inflammatory response. The inflammatory lesion in beige mice contained a predominance of mononuclear cells, whereas their littermates responded with a typical mixed granulomatous infiltrate. Collectively, these results provide evidence supporting the hypothesis that resistance to C. immitis infection involves two primary cell populations, one under the direct influence of T-cells and the other independent of T-lymphocytes.