Coccidioidomycosis is a rare, often subclinical infection in domestic animals caused by the fungus Coccidioides immitis. Because of an apparent high incidence of coccidioidomycosis in Przewalski's horses (Equus przewalskii) housed at a single facility, necropsy records and biomaterials from animals that died between 1984 and 2000 were reviewed (n = 30, 15 males, 15 females). Coccidioidomycosis was the leading cause of death (33%) in this population with lesions in the lungs and tracheobronchial lymph nodes of all animals and variable involvement of the skeletal muscle, heart, kidney, liver, skin, brain, spinal cord, spleen, as well as other regional lymph nodes. At the time of death, affected horses tended to be younger than unaffected animals, were from multiple lineages, and males were over represented. During the same time period, no other exotic equids (n = 76) housed at the same facility were diagnosed with coccidioidomycosis, suggesting that environmental factors are not the sole cause of the high incidence in E. przewalskii. Numbers of the lymphocyte subsets (CD3, CD4, CD5, CD8, CD21+ cells) quantified by flow cytometry were similar between Przewalski's horses and domestic horses (Equus caballus). Although responses of lymphocyte blastogenesis assays were similar between Przewalski's (n = 5) and domestic horses (n = 5) in response to the T cell mitogen concanavalin A, lymphocytes from two of the Przewalski's horses failed to proliferate in response to Coccidioides. One of these horses had systemic disease and the second developed coccidioidomycosis 2 yr later. These results suggest that the immune system of some Przewalski's horses fails to respond appropriately to Coccidioides.