ABSTRACT: Depression and substance use, the most common comorbidities with HIV, are both associated with poor treatment adherence. Injection drug users comprise a substantial portion of individuals with HIV in the United States and globally. The present study tested cognitive behavioral therapy for adherence and depression (CBT-AD) in patients with HIV and depression in active substance abuse treatment for injection drug use.This is a 2-arm, randomized controlled trial (N = 89) comparing CBT-AD with enhanced treatment as usual (ETAU). Analyses were conducted for two time-frames: (a) baseline to post-treatment and (b) post-treatment to follow-up at 3 and 6 months after intervention discontinuation.At post-treatment, the CBT-AD condition showed significantly greater improvement than ETAU in MEMS (electronic pill cap) based adherence, ?slope = 0.8873, t(86) = 2.38, p = .02; dGMA-raw = 0.64, and depression, assessed by blinded assessor: Mongomery-Asberg Depression Rating Scale, F(1, 79) = 6.52, p < .01, d = 0.55; clinical global impression, F(1, 79) = 14.77, p < .001, d = 0.85. After treatment discontinuation, depression gains were maintained, but adherence gains were not. Viral load did not differ across condition; however, the CBT-AD condition had significant improvements in CD4 cell counts over time compared with ETAU, ?slope = 2.09, t(76) = 2.20, p = .03, dGMA-raw = 0.60.In patients managing multiple challenges including HIV, depression, substance dependence, and adherence, CBT-AD is a useful way to integrate treatment of depression with an adherence intervention. Continued adherence counseling is likely needed, however, to maintain or augment adherence gains in this population.