Existing research examining the role of psychopathology on HIV risk behaviors has relied heavily upon cross-sectional data, making it difficult to assess causal relationships. This paper uses longitudinal data to examine the relationship between depressive symptoms and sexual risk behaviors in a community sample of 332 inner-city drug users. Results from repeated measures analysis using generalized estimating equations suggest that high depressive symptoms may be causally related to having sex with multiple partners (odds ratio = 1.55, CI: 1.12, 2.14) and having sex with injection drug users (odds ratio = 1.57, CI: 1.11, 2.22) and crack users (odds ratio = 1.37, CI: 1.02, 1.86). Findings support greater attention to depressive symptoms in HIV prevention interventions for illicit drug users to reduce sexual risk behaviors.