Depression and depressive symptoms mediate the association between drug use and HIV risk. Yet, there are few interventions that target depressive symptoms and HIV risk for people who use drugs (PWUD). This study was a randomized controlled trial of an integrated cognitive behavioral therapy and HIV prevention intervention to reduce depressive symptoms, injection risk behaviors and increase condom use in a sample of urban people who used heroin or cocaine in the prior 6 months. A total of 315 individuals aged 18-55, who self-reported at least one HIV drug and sex risk behavior and scored ≥16 and <40 on the Centers for Epidemiologic Studies-Depression (CES-D) scale were randomized using a two-block design, stratified by sex to ensure equivalent numbers, to a 10 session intervention arm (n = 162) or a single session control arm (n = 153). The outcomes of interest were decreases in CES-D score and injection risk behaviors and increases in condom use. The sample was majority African American (85%) and unemployed (94%). Nearly half (47%) reported injection in the prior 6 months and only 19% were taking medication for depression. Follow-up assessments were conducted at 6 and 12 months. Retention at 12 months was 94%. Intervention arm was associated with statistically significantly lower CES-D score at 12 month compared to control. No differences were observed between arms in injection risk. At 6 month, intervention was associated with greater odds of condom use with non-main partner. These findings suggest the potential role of the integrated intervention in reducing depressive symptoms, but weak impact on HIV risk. This trial is registered with ClinicalTrials.gov under the title "Neighborhoods, Networks, Depression, and HIV Risk" number NCT01380613.