Cell-mediated immunity is critical to host defenses against the fungal infection cryptococcosis. Here, two functions critical to effective cell-mediated immunity (CMI), lymphoproliferation and cytokine release, were studied in Cryptococcus neoformans-stimulated peripheral blood mononuclear cells (PBMC) from seven healthy donors (controls) and two patients with cryptococcosis. PBMC responses to C. neoformans were compared with responses to Candida albicans. Control and patient PBMC had significant lymphoproliferation in response to whole C. neoformans, with peak proliferation seen following 8 days of culture, but only patient PBMC proliferated when stimulated with C. neoformans mannoprotein. C. neoformans-stimulated control PBMC released IL-2, IFN-gamma, and IL-10 into the supernatant with peak or near peak concentrations of these three cytokines generally seen by day 1. Release of IL-4 was low or undetectable. In contrast, C. neoformans-stimulated patient PBMC released IFN-gamma, which peaked on day 7, as well as IL-4, IL-10, and in one of two patients, IL-2. Cytokine release occurred later in patient (compared with control) PBMC. Lymphoproliferation and cytokine release were similar comparing control PBMC stimulated with C. neoformans versus Candida albicans. Thus, the magnitude and kinetics of the lymphoproliferative response to whole C. neoformans is similar comparing PBMC from controls and patients, but the cytokine profiles differ. Moreover, the capacity of patient PBMC to respond to soluble mannoprotein lends support to studies of mannoprotein components as vaccine candidates.