INTRODUCTION: Substance use disorders (SUD) frequently co-occur with posttraumatic stress disorder (PTSD). Little is known, however, about how individuals with a single SUD diagnosis (relating to only one substance) compare to individuals with poly-SUD diagnoses (relating to more than one substance) on substance use and PTSD treatment outcomes. To address this gap in the literature, we utilized data from a larger study investigating a 12-week integrated, exposure-based treatment (i.e., Concurrent Treatment of PTSD and Substance Use Disorders using Prolonged Exposure, or COPE) to examine treatment outcomes by single vs. poly-SUD status. METHOD: Participants were 54 Veterans (92.6% male, average age = 39.72) categorized as having single SUD (n = 39) or poly-SUD (n = 15). T-tests characterized group differences in baseline demographics and presenting symptomatology. Multilevel models examined differences in treatment trajectories between participants with single vs. poly-SUD. RESULTS: Groups did not differ on baseline frequency of substance use, PTSD symptoms, or treatment retention; however, individuals with poly-SUD evidenced greater reductions in percent days using substances than individuals with a single SUD, and individuals with a single SUD had greater reductions in PTSD symptoms than individuals with poly-SUD over the course of treatment. DISCUSSION: The findings from this exploratory study suggest that Veterans with PTSD and co-occurring poly-SUD, as compared to a single-SUD, may experience greater improvement in substance use but less improvement in PTSD symptoms during integrated treatment. Future research should identify ways to enhance treatment outcomes for individuals with poly-SUD, and to better understand mechanisms of change for this population.