Cryptococcal meningoencephalitis is considered rare in HIV-negative individuals. In Madagascar, the epidemiology of cryptococcosis has not yet been well described, neither in immunocompetent nor in immunocompromised patients. We report here the first Malagasy detailed case of cryptococcal meningoencephalitis in a non-HIV immunocompromised adult patient carrying a low fluconazole susceptibility isolate. We emphasize the importance of early and accurate diagnosis to meet the challenges of managing cryptococcosis in developing countries.