Abstract: Objective: PTSD and substance use disorders (SUD) frequently co-occur among veterans. Integrated exposure-based treatments, such as Concurrent Treatment of PTSD and SUD Using Prolonged Exposure (COPE), are efficacious in reducing PTSD and SUD symptoms and posttraumatic emotions. This study examines whether guilt and anger (a) decreased in a randomized clinical trial comparing COPE with Relapse Prevention (RP) therapy for SUD and (b) mediated PTSD and SUD symptom reductions or vice versa. Method: Veterans (90.1% men) diagnosed with PTSD and SUD were randomized to 12 sessions of COPE (n = 54) or RP (n = 27). Guilt and anger were assessed at 10 time points during treatment. Multilevel linear models assessed changes in guilt and anger across treatments and lagged multilevel mediation analyses assessed within-subject change in guilt and anger predicting PTSD and percent days of substance use, and vice versa. Results: Guilt (B = -.12, SE = .02, p < .001) and anger (B = -.13, SE = .02, p < .001) improved in both treatments, however guilt was significantly lower in Sessions 7 through 11 among veterans receiving COPE. Improvement in guilt mediated PTSD symptom improvement in both treatment groups (B = -.08, SE = .04, 95% CI [-.16, -.01]), and PTSD symptom improvement mediated anger reduction in COPE (B = -.03, SE = .01, 95% CI [-.06, -.01]). The substance use models were insignificant. Conclusions: Among veterans, integrated, trauma-focused treatments may be associated with greater guilt (directly) and anger (indirectly) reductions due to processing trauma. (PsycInfo Database Record (c) 2023 APA, all rights reserved).