Undesirable tissue reactions, resulting from the subcutaneous injection of 150 viable arthrospores of Coccidioides immitis (strain D-76), could be reduced by injecting formalin-killed arthrospores before injecting the viable organisms. By the termination of the study, 6 and 12% of these vaccinated animals exhibited ulceration and lymphadenopathy, respectively, as compared with 100 and 83% of animals receiving only the viable vaccine. Agar/gel immunodiffusion precipitin titers of approximately 1:64 were evident 3 months after vaccination in animals receiving both vaccines as compared with 1:128 in those injected with the viable vaccine only. The data indicated that the somatic reactions resulting from injection of a viable vaccine could be eliminated by preinjection of a killed vaccine. Although the tissue reactions were reduced by this treatment, respiratory challenge (7,500 strain Cash arthrospores) six months after vaccination indicated that the protective effect of the viable vaccine was also impaired. All animals receiving both vaccines developed mild pulmonary coccidioidomycosis, whereas only 50% of the animals receiving the viable vaccine only were infected. In addition, the group receiving both vaccines demonstrated a more rapid and higher postchallenge precipitin titer. All vaccinated animals (those receiving the killed, the viable, or a combination of the two vaccines) survived for 4 months after challenge, as compared with 88% mortality (50% within 14 days) in the nonvaccinated controls.