This observational cohort study of 4,160 AIDS patients hospitalised in a single institution in northern Italy between January 1985 and December 1999 was carried out in order to assess the natural history of cryptococcosis, the epidemiological trend of this opportunistic infection, the risk factors predictive of death at 10 weeks, the response to therapy, and autopsy findings. Cryptococcosis was diagnosed in 177 (4.2%) patients and was the AIDS-defining disease in 2.8% of cases. Its prevalence decreased significantly over time (from 6.4% in the period 1985-1989 to 5.7% in 1990-1993, 3.1% in 1994-1996, and 1.9% in 1997-1999, P <0.0001). Although neurologic disease was the most frequent clinical picture, a significant proportion of the patients (24.2%) presented with extraneural cryptococcosis. In a Cox multivariate analysis, high titres of cerebrospinal fluid antigen (>5000) and drug addiction were predictive of death at 10 weeks. A complete clinical and mycological response was achieved in 60.8% of the treated patients, with the highest response rate being observed in those treated with amphotericin plus flucytosine (66.6%). Cryptococcosis relapsed in 12.8% of patients on secondary prophylaxis. Autopsy findings demonstrated that cryptococcosis is a disseminated disease, but long-term antifungal treatment may be able to eradicate it in a subgroup of patients.