To examine trends in progressive multifocal leukoencephalopathy (PML) mortality in the United States, we analyzed PML death rates and deaths for 1979 through 1994, using US multiple cause-of-death data. During the 16-year study period 3,894 PML deaths were reported. The age-adjusted death rate increased more than 20-fold, from less than 0.2 per million persons before 1984 to 3.3 per million persons in 1994. The increase was attributable to infection with human immunodeficiency virus (HIV) which was recorded on 2,267 (89.0%) of 2.546 death records from 1991 through 1994. PML age-adjusted death rates increased abruptly for all males beginning in 1984 and for black females in 1990. Only a small increase was observed for white females. In 1994, PML was reported in 2.1% of white males who died with HIV-associated disease compared with 1.2% of white females and 1.0% of black males and females who died of similar causes. The epidemic of PML deaths is increasing in parallel with the AIDS epidemic. The increase in HIV-associated PML deaths, first noted among males, has also become apparent among females and probably reflects the increasing importance of drug use and heterosexual transmission of HIV. The reason for the higher prevalence of PML among white males with HIV infection is unknown.