To determine the incidence of cryptococcosis and its risk factors among human immunodeficiency virus (HIV)-infected persons, population-based active surveillance was conducted in four US areas (population, 12.5 million) during 1992-1994, and a case-control study was done. Of 1083 cases, 931 (86%) occurred in HIV-infected persons. The annual incidence of cryptococcosis per 1000 among persons living with AIDS ranged from 17 (San Francisco, 1994) to 66 (Atlanta, 1992) and decreased significantly in these cities during 1992- 1994. Among non-HIV-infected persons, the annual incidence of cryptococcosis ranged from 0.2 to 0.9/100.000. Multivariate analysis of the case-control study (158 cases and 423 controls) revealed smoking and outdoor occupations to be significantly associated with an increased risk of cryptococcosis; receiving fluconazole within 3 months before enrollment was associated with a decreased risk for cryptococcosis. Further studies are needed to better describe persons with AIDS currently developing cryptococcosis in the era of highly active antiretroviral therapy.