Posttraumatic stress disorder (PTSD) and other Axis I comorbidity among women with substance use disorders (SUDs) appear similarly prevalent and are associated with comparable negative clinical profiles and treatment outcomes. The relative contribution of comorbid PTSD vs other Axis I psychiatric disorders to clinical characteristics is largely unexamined, however, despite theory and empirical data indicating that PTSD and SUDs may have a unique relationship that confers specific risk for clinical severity and poor treatment outcome. In a sample of pregnant, opioid- and/or cocaine-dependent women entering substance abuse treatment, women with PTSD (SUD-PTSD; n = 23) were compared to those with other Axis I comorbidity (SUD-PSY; n = 45) and those without Axis I comorbidity (SUD-only; n = 37). Data were collected via face-to-face interviews and urinalysis drug assays. Although the study groups had similar substance use severity, the SUD-PTSD group was more likely to report suicidality, aggression, and psychosocial impairment than both the SUD-PSY and SUD-only groups. Findings indicate treatment considerations for substance-dependent women with PTSD are broader and more severe than those with other Axis I conditions or substance dependence alone.