BACKGROUND: To test whether an integrated prolonged exposure (PE) approach could address posttraumatic stress disorder (PTSD) symptoms effectively in individuals with co-occurring substance use disorders (SUD), we compared concurrent treatment of PTSD and SUD using PE (COPE) to relapse prevention therapy (RPT) for SUD and an active monitoring control group (AMCG). METHODS: We conducted a randomized 12-week trial with participants (n = 110; 64% males; 59% African Americans) who met Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision criteria for full or subthreshold PTSD and SUD. Participants were randomly assigned to COPE (n = 39), RPT (n = 43), or AMCG (n = 28). RESULTS: At the end-of-treatment, COPE and RPT demonstrated greater reduction in PTSD symptom severity relative to AMCG (COPE-AMCG = -34.06, p < 0.001; RPT-AMCG = -22.58, p = 0.002). Although the difference between COPE and RPT was not significant in the complete sample, the subset of participants with full (vs. subthreshold) PTSD demonstrated significantly greater reduction of PTSD severity in COPE relative to RPT. Both treatments were superior to AMCG in reducing the days of primary substance use (COPE-AMCG = -0.97, p = 0.01; RPT-AMCG = -2.07, p < 0.001). Relative to COPE, RPT showed significantly more improvement in SUD outcome at end-of-treatment (RPT-COPE = -1.10, p = 0.047). At 3-month follow-up, COPE and RPT maintained their treatment gains and were not significantly different in PTSD severity or days of primary substance use. CONCLUSION: COPE and RPT reduced PTSD and SUD severity in participants with PTSD + SUD. Findings suggest that among those with full PTSD, COPE improves PTSD symptoms more than a SUD-only treatment. The use of PE for PTSD was associated with significant decreases in PTSD symptoms without worsening of substance use.