Cryptococcus neoformans is a pathogenic yeast that causes life-threatening pneumonia and meningitis in AIDS patients. Natural killer (NK) cells are important effector cells that directly recognize and kill C. neoformans via perforin-dependent cytotoxicity. Although it had previously been demonstrated that, NK cells from HIV-infected patients have defective anticryptococcal activity, and IL-12 restored the activity, almost nothing was known of the mechanisms causing this defect or how IL-12 restored the defect. By examining the sequential steps in NK cell killing of Cryptococcus, I determined that NK cells from HIV-infected patients had lower intracellular perforin expression, defective perforin release and defective ability to polarize perforin to the fungal synapse. Importantly, treatment of NK cells from HIV-infected patients with IL-12 reversed these defects and restored the defective anticryptococcal activity. Thus, there are multiple defects in the cytolytic machinery of NK cells from HIV-infected patients, which result in the defective anticryptococcal activity, and these defects can be reversed with IL-12.