Two hundred Hartley-inbred guinea pigs were infected intratracheally with 50 viable arthrospores of Coccidioides immitis. At weeks 1 through 10 postinfection, groups of 20 guinea pigs were assayed for skin test, macrophage migration inhibitory factor (MIF), and lymphocyte transformation (LT) responses to coccidioidin. Forty-eight hours after skin testing and just before MIF and LT assays, blood was obtained for complement-fixing (CF) antibody titers and the animals were autopsied to assess the extent of fungal dissemination. Immunological assays established that skin tests and MIF responses converted within 3 weeks of infection. LT responses were not demonstrable until week 5. Dissemination of C. immitis to the liver or spleen was an early event, with 21% of guinea pigs positive by week 2 and 70% positive by week 5. CF antibody titers were demonstrable at week 5, increased logarithmically through week 7, then increased at a slower rate thereafter. Concomitant with the decreased rate of antibody production, guinea pigs began to clear C. immitis from their extrapulmonary tissues. Skin test responses peaked at 6 weeks postinfection when CF antibody titers were less than or equal to 1:16 and then plateaued with increased CF titers. Although this overall immunological profile is consistent with the disease in humans, there was not a direct correlation between CF antibody titer and dissemination to the liver or spleen, nor was there an inverse correlation between CF antibody titers and skin test or MIF responses. Rather, CF antibody titers and cell-mediated immune responses were equally demonstrable in guinea pigs with disseminated or nondisseminated disease.