To determine which lymphocytes are required for vaccine-induced immunity to coccidioidomycosis, we used a temperature-sensitive mutant of Coccidioides immitis to immunize mice lacking subsets of lymphocytes or specific cytokines and infected the mice 4 weeks later with virulent C. immitis. After 2 weeks, we determined the number of fungi in their lungs and spleens. Vaccine-induced immunity required αβ T lymphocytes. β-2 microglobulin knockout (KO) mice were protected by immunization, and we transferred protection using CD4⁺ T cells from immunized mice. However, vaccination also protected CD4⁺ KO mice, which suggests that CD8⁺ T cells played a role in vaccine-induced immunity, even though they were not required. We adaptively transferred protection using spleen cells from immunized CD4⁺ KO mice to nonimmune B6 mice, but CD8⁺-depleted spleen cells did not protect against infection. Recipients of spleen cells from immunized CD4⁺ KO mice had 6 times more tumor necrosis factor (TNF)–α mRNA in their lungs than did mice that received nonimmune spleen cells, and TNF receptor–1 KO mice were not fully protected by immunization. These results show that both CD4⁺ and CD8⁺ T cells can protect against coccidioidomycosis and that TNF-α is a necessary component of the acquired immune response