Cell-mediated immunity plays an important role in immunity to the pathogenic fungus Cryptococcus neoformans. However, the antigen specificity of the T-cell response to C. neoformans remains largely unknown. In this study, we used two approaches to determine the antigen specificity of the T-cell response to C. neoformans. We report here that a diverse T-cell receptor (TCR) Vβ repertoire was maintained throughout the primary response to pulmonary C. neoformans infection in immunocompetent mice. CD4⁺ T-cell deficiency resulted in relative expansion of all CD8⁺ T-cell subsets. During a secondary immune response, preferential usage of a TCR Vβ subset in CD4⁺ T cells occurred in single individuals, but the preferences were “private” and not shared between individuals. Both CD4⁺ and CD8⁺ T cells from the secondary lymphoid tissues of immunized mice proliferated in response to a variety of C. neoformans antigens, including heat-killed whole C. neoformans, culture filtrate antigen, C. neoformans lysate, and purified cryptococcal mannoprotein. CD4⁺ and CD8⁺ T cells from the secondary lymphoid tissues of mice undergoing a primary response to C. neoformans proliferated in response to C. neoformans lysate. In response to stimulation with C. neoformans lysate, lung CD4⁺ and CD8⁺ T cells produced the effector cytokines tumor necrosis factor alpha and gamma interferon. These results demonstrate that a diverse T-cell response is generated in response to pulmonary C. neoformans infection.