Cognitive behavioral therapy for adherence and depression (CBT-AD) in HIV improves both adherence and depression outcomes relative to enhanced treatment as usual (ETAU). However, in persons with injection drug use (PWIDU) histories, adherence gains seen during treatment have not been maintained postintervention. Therefore, we examined whether heroin or cocaine use at study entry moderated acquisition or maintenance of adherence gains after CBT-AD. HIV-positive adults in treatment for opioid dependence (n = 89) were randomly assigned to CBT-AD or ETAU and completed 3-, 6-, and 12-month assessments. Participants were majority male (61%), white (48%), and heterosexual (79%). Hierarchical linear modeling was used to evaluate whether heroin or cocaine use at baseline interacted with intervention assignment to predict change in adherence during active treatment and follow-up. CBT-AD-related improvement in adherence during the active intervention period did not vary by baseline substance use. However, cocaine use (but not heroin use) at baseline interacted with intervention assignment to predict a significant decline in follow-up adherence (cocaine use × group condition coefficient = -0.77, t = -2.44, p = 0.02) such that by 12 months, adherence among CBT participants was significantly lower among those who used cocaine (45.0%) compared to those who did not (72.3%; t = 2.50, p = 0.018). HIV-positive PWIDU who use heroin or cocaine at baseline can benefit from the CBT-AD intervention to improve adherence to antiretroviral therapy; therefore, providers should not withhold an active psychosocial treatment for HIV-positive PWIDU who are using. Cocaine use at baseline may limit the degree to which gains are maintained postintervention, and therefore, booster sessions may be needed.