Comparisons of the course of coccidioidomycosis in two strains of inbred mice established that BALB/c mice are significantly more susceptible to pulmonary infection with Coccidioides immitis than are DBA/2 mice. The susceptibility of BALB/c mice does not reside in their inability to mount a delayed-type hypersensitivity response to C. immihis antigen. That is, BALB/c mice manifested footpad hypersensitivity to coccidioidin early during the course of disease, to a level comparable to that of DBA/2 mice. In contrast to the more resistant DBA/2 mouse strain, however, BALB/c mice developed anergy by day 15 postinfection. Suppression of the delayed-type hypersensitivity response was not specific for C. immitis antigen, as evidenced by the finding that BALB/c mice immunized with mycobacterial purified protein derivative prior to infection with C. immitis were suppressed in their footpad response to mycobacterial antigen at day 15 postinfection. Taken together, these results establish that genetically determined susceptibility to this fungus is associated with an acquired suppression of cell-mediated immune reactivity. Coccidioidomycosis is a mycotic disease caused by the diphasic fungus Coccidioides immitis. Primary infection is acquired via inhalation of mycelial-phase arthroconidia, which convert to endosporulating spherules in host tissue. Manifestations of the disease range from a benign, selflimited pulmonary infection to a severe, progressive, and often fatal mycosis involving pulmonary and extrapulmonary tissues. Host defense against C. immitis is T-cell dependent, transferable by immune T cells, independent of antibody, and correlative with delayed-type hypersensitivity (DTH) to coccidioidal antigens (1-3). Thus, in humans and experimental animals, primary self-limited disease is commonly associated with strong cell-mediated immune responses to C. immitis, and conversely, progressive coccidioidomycosis is associated with depressed cell-mediated immunity (CMI)