In this study, we analyzed the possibility that Indinavir (IDV), a well-known protease inhibitor (PI) used in highly active antiretroviral therapy, could affect immune response against the opportunistic fungus Cryptococcus neoformans. In particular, the quality of dendritic cell (DC) response was analyzed. The results reported here show that IDV treatment induces an expansion of DC with CD8alpha phenotype in spleens of infected hosts. Splenic CD11c+ DC expressed elevated costimulatory molecules such as CD40 and CD80, showed an increased expression of mRNA for proinflammatory cytokines, and secreted abundant IL-12. Integration of all aforementioned regulatory effects results in development of an efficient, T cell-protective response that reflects a consistent reduction in fungus colonization at a cerebral level. These results could help to elucidate the immunoregulatory activity of PI and point out the beneficial effects of IDV in regulating DC functions and antifungal activity. Therefore, although new PI are being introduced in the clinical setting, nevertheless, given its low cost and proven efficacy, IDV could still be considered a potential key compound in the treatment of HIV in resource-limited settings.