The annual incidence of cryptococcosis during 1981-2000 was determined in subscribers of a large integrated health care program in Northern California and in those among them who were HIV positive. The incidence of cryptococcosis had been measured in this setting in the previous decade. The 20-year incidence per million person-years was 19.0 in males and 2.6 in females. In males, annual incidence rose sharply but irregularly from 1981 to 1992, then decreased irregularly. In females, trends were less marked, with maximum incidence in 1997. In HIV-positive patients cryptococcosis incidence was highest in 1981-85 and decreased thereafter in men. In women, maximum incidence occurred in 1986-90 and was followed by a decrease. Cryptococcosis was rare in the non-predisposed. Thus, cryptococcosis incidence increased markedly in men early in the AIDS epidemic, and began to decrease in both male and female HIV-positive patients well before highly active antiretroviral therapy became available.