Individuals with posttraumatic stress disorder (PTSD) exhibit deficits in cognitive and emotional processes. PTSD severity is positively associated with anxiety sensitivity (AS) and difficulties in emotion regulation, and difficulties in emotion regulation mediate the relation between AS and PTSD. However, previous research has not examined the interactive nature of these variables. Associations between PTSD, AS, and difficulties in emotion regulation were examined in patients with PTSD in a residential substance use treatment program (N = 120). Conditional process analyses indicated an interactive effect of difficulties in emotion regulation and AS for predicting PTSD symptom severity. For individuals high in emotion regulation difficulties, PTSD symptom severity was high regardless of level of AS; conversely, for individuals high in AS, increased PTSD severity was observed regardless of level of emotion regulation difficulties. Results suggest directions for future research, including examination of whether targeting patient-specific cognitive-affective processes enhances PTSD treatment response among substance-dependent individuals.