Previous investigations have demonstrated that macrophages play a critical role in the first‐line cellular defense mechanism against infection with Cryptococcus neoformans. In the present study, to elucidate the way in which anticryptococcal activity of macrophages is regulated at the site of infection, pulmonary intraparenchymal macrophages were directly analyzed for expression of their surface molecules and their phagocytic activities against the organism, and the effects of depletion of T cells and endogenous IFN‐γ in vivo on these parameters were examined. In the lungs of mice intratracheally inoculated with heat‐killed C. neoformans, macrophages were activated, as indicated by augmented expression of MHC class II, intercellular adhesion molecule‐1 (ICAM‐1) and Fc receptor (FcR), and about two‐thirds of macrophages were found to have ingested an average of 3.77 ± 0.12 yeast cells per macrophage. In mice depleted of both CD4⁺ and CD8⁺ T cells by injecting the specific monoclonal antibodies (mAbs) or anti‐IFN‐γ mAb, not only augmentation of the expression of macrophage activation markers but also phagocytosis of C. neoformans was significantly reduced. These results suggest that anticryptococcal activity of macrophages is regulated by IFN‐γ endogenously produced by T cells. Additionally, treatment with IFN‐γ were shown to significantly prolong the survival time of mice infected with viable C. neoformans. Additionally, preimmunization with heat‐killed C. neoformans significantly prolonged the survival time of mice which received the following infection.