The resistance of mice to coccidioidomycosis was found to be dependent on lymphoid cells. Thus, spleen cells from mice immunized with killed spherules of Coccidioides immitis, when transferred to irradiated (500 R) recipients, conferred upon the recipient mice resistance to infection with C. immitis. Prior incubation of these spleen cells with anti-theta serum in the presence of complement abrogated their capacity to protect the recipients from infection with C. immitis. Adult thymectomized mice, which had been irradiated (800 R) and reconstituted with bone marrow from normal mice, were more susceptible to infection with arthrospores than were nonthymectomized, irradiated bone marrow-reconstituted controls. Genetically homozygous athymic ("nude") mice died after infection with a dose of arthrospores that was sublethal for their heterozygote counterparts possessing a thymus, or for normal mice. The results indicate that a functioning T-cell population is an essential component for effective immunity to C. immitis.