We studied the effects of cyclosporine on experimental cryptococcal meningitis. Like cortisone, cyclosporine depressed the highly effective defense mechanisms of normal rabbits against inoculated Cryptococcus neoformans, causing them to develop progressive, fatal cryptococcal meningitis. Unlike cortisone, which causes a striking reduction in leukocytes in cerebrospinal fluid, cyclosporine depressed mononuclear cell function rather than numbers. Interleukin 2, a primary target for the immunodepressive action of cyclosporine, appears to be of central importance in central nervous system defenses against cryptococci. The findings suggest that humans receiving cyclosporine are likely to suffer increased incidence of cryptococcal infection.