This study investigated the association between cumulative exposure to multiple traumatic events and psychological distress, as mediated by problematic substance use and impaired psychosocial resources. A sample of HIV-positive and HIV-negative women were assessed for a history of childhood and adult sexual abuse and non-sexual trauma as predictors of psychological distress (i.e., depression, non-specific anxiety, and posttraumatic stress), as mediated by problematic alcohol and drug use and psychosocial resources (i.e., social support, self-esteem and optimism). Structural equation modeling confirmed that cumulative trauma exposure is positively associated with greater psychological distress, and that this association is partially mediated through impaired psychosocial resources. However, although cumulative trauma was associated with greater problematic substance use, substance use did not mediate the relationship between trauma and psychological distress.