This study assessed the association between longitudinal patterns of illicit drug use and clinical progression of human immunodeficiency virus (HIV) disease. Confidential computer-based interviews, which addressed illicit drug use and other factors, were completed by HIV-infected participants in Baltimore, Maryland, at 6-month intervals from 1998 onward. To assess this association, the authors used a random-effects model in which clinically defined opportunistic conditions were linked to self-reported periods of drug use, enabling four categories of drug use to be distinguished: nonusers, intermittent users during abstinent periods, intermittent users during active periods, and persistent users. Included in the analysis were 1,851 participants who completed > or = 1 survey. For participants who used drugs intermittently over time, the risk of developing new opportunistic conditions during periods of abstinence was similar to that for those who never used drugs (odds ratio = 1.2, 95% confidence interval: 0.9, 1.7). In contrast, compared with that for nonusers, the risk of opportunistic infection was significantly higher for intermittent drug users during periods of active use (odds ratio = 2.2, 95% confidence interval: 1.4, 2.9) and for persistent drug users (odds ratio = 1.9, 95% confidence interval: 1.2, 2.8). Active drug use is temporally linked to HIV disease progression and mortality. Effectively targeting and treating active substance abuse in HIV treatment settings may provide a mechanism to improve clinical outcomes.