A population-based register of cases of cryptococcosis in patients treated in Victoria, Australia, over a 10-year period was established for studying the epidemiologic and clinical features of infection with Cryptococcus neoformans and its two varieties, gattii and neoformans. One hundred thirty-three cases of cryptococcosis were entered on the register; the incidence was 3.0 cases per 1 million population per year, a rate that increased to 5.0 cases per 1 million population per year over the decade as a result of the AIDS epidemic. There was a distinct association between immune status and C. neoformans variety: all C. neoformans variety gattii infections occurred in healthy hosts and 90% of C. neoformans variety neoformans infections occurred in immunosuppressed hosts. Meningitis was the commonest manifestation, with focal CNS and pulmonary lesions occurring primarily in healthy hosts with C. neoformans variety gattii infection; isolation of C. neoformans from blood and urine was associated with immunosuppression and C. neoformans variety neoformans infection. The mortality among patients with C. neoformans variety neoformans infection was high, while none of those patients with C. neoformans variety gattii died but often had neurological sequelae that required surgery and prolonged therapy. These findings appear to be related to variety-specific interactions between host and parasite and warrant further epidemiologic and immunologic study.