In a multicenter cohort study of homosexual men, the proportion of seropositives at enrollment who developed the acquired immunodeficiency syndrome (AIDS) during the following 18 months ranged from 5.5% to 8.2% in 1597 alcohol drinkers vs 9.2% in 109 nondrinkers with no clear trend according to use, and from 6.3% to 9.6% for 1662 users vs 7.2% for 83 nonusers of psychoactive drugs prior to enrollment. Among seropositive men with low initial T helper lymphocyte counts, those who continued to use drugs showed no significantly higher 18-month risk of AIDS than nonusers (13% vs 10%); the corresponding risks were 13% and 15%, respectively, for continued heavier vs continued lighter consumption of alcohol. No other manifestations of immunodeficiency were positively associated with substance use prior to enrollment. Prior use was not associated with low mean T helper cell counts at enrollment, and continued drug or alcohol use after enrollment was not associated with greater subsequent decline in counts. As used in a large cohort of homosexual men, psychoactive substances did not enhance the progression of human immunodeficiency virus infection.