Cryptococcus neoformans is the most common cause of fungal meningitis in HIV and non-HIV-infected patients. The organism has a worldwide distribution, with cases typically occurring among patients with well-recognized specific underlying disorders associated with dysfunction of cell- mediated immunity. While the therapy for disease was studied extensively in the 1970s and the 1980s among non-HIV-infected individuals, most of the recently published data have concerned therapy for central nervous system cryptococcosis in HIV-infected patients. As a result, the current approach to therapy for central nervous system cryptococcosis in the non-HIV-infected patient represents a hybrid of the established "gold standard," which includes at least 6 weeks of combination therapy with amphotericin B and 5-flucytosine, and the more contemporary regimen, which consists of 2 weeks of induction therapy with an amphotericin B-containing regimen followed by fluconazole. Clearly, well-designed prospective studies are needed to define the best approach to therapy in these patients, but until then, we must rely on the results of the existing clinical trials and carefully interpret the results of the available retrospective data. At present, amphotericin B (deoxycholate or lipid-associated) is recommended as initial therapy for all non-HIV-infected patients with proven or suspected cryptococcal meningitis. Fluconazole plays an important role in consolidation therapy and among selected patients who require long-term chronic suppression. The potential role of the newer triazoles (voriconazole and posaconazole) is undetermined.