Although mortality rates among HIV-infected populations have declined with the advent of combination antiretroviral therapy (ART), patients with substance use disorders have benefited less from these therapies. While adherence to ART has been well studied, less is known about factors associated with discontinuation of ART. The aim of this study is to investigate predictors of discontinuation of ART in HIV-infected patients with alcohol problems, focusing on their substance use and depressive symptoms. The study cohort (n=266) was prospectively assessed with biannual standardised interviews between 2001 and 2005. Four predictor variables (cocaine, heroin, heavy alcohol use and substantial depressive symptoms) were assessed six months prior to the outcome (ART discontinuation). Longitudinal logistic regression models examined the association between predictor variables and ART discontinuation adjusting for age, gender, race/ethnicity, homelessness, CD4, HIV RNA and HIV Symptom Index. Subjects were 77% male; 43% black; 22% homeless; 45% used cocaine; 20% used heroin; 29% had heavy alcohol use; and 40% had substantial depressive symptoms. Discontinuation occurred in 135 (17%) of the observations (n=743). In bivariate analyses, cocaine use, heroin use and depressive symptoms were significantly associated with ART discontinuation but heavy alcohol use was not. In the multivariable model, substantial depressive symptoms (adjusted odds ratio (AOR)=1.66; 95% confidence interval (CI): 1.04, 2.65) but not cocaine (AOR=1.28; 95%CI: 0.76, 2.16) or heroin use (AOR=1.27 95%CI: 0.66, 2.44), remained significantly associated with ART discontinuation. Among HIV-infected adults with alcohol problems, depressive symptoms, but not substance use, predicted subsequent ART discontinuation. Recognition and treatment of depressive symptoms in this population may result in better maintenance of ART and its associated clinical benefits.