Abstract: Substance use disorders (SUDs) are prevalent among military veterans, with severe substance use and polysubstance use disorder (poly-SUD) related to worse clinical outcomes. Although the relation between posttraumatic stress disorder (PTSD) and SUD is well established in veterans, less is known about how other common psychiatric conditions (e.g., major depressive disorder [MDD], generalized anxiety disorder [GAD]) or traumatic exposures (e.g., sexual assault) may collectively affect SUD severity and poly-SUD. The current study examined the association between MDD, GAD, and sexual assault history on two outcomes of SUD severity: total SUD symptom count (i.e., SUD severity) and number of diagnosed SUDs (poly-SUD). Two-hundred and fifty-four veterans engaging in residential treatment participated in a semi-structured diagnostic interview (Structured Clinical Interview for the DSM-5, Research Version) to assess for psychiatric diagnoses. Veterans also completed the PTSD Checklist for DSM-5 and the Life Events Checklist to assess for PTSD symptoms and trauma exposures, respectively. Analysis of covariance tested for main and interaction effects of MDD, GAD, and sexual assault history on SUD severity and poly-SUD, controlling for PTSD symptoms. A three-way interaction demonstrated that veterans with MDD, GAD, and a sexual assault history had significantly higher SUD severity and poly-SUD than those without all risk factors. These findings highlight the cumulative risk for severe substance use and poly-SUD for veterans with comorbid MDD and GAD and sexual assault histories who are engaged in residential treatment. Clinical recommendations include broader assessment of psychiatric conditions and integrated treatment that addresses comorbid psychopathology in addition to substance use. Future research should directly examine the chronology and motivation behind severe poly-SUD in veterans with these comorbidities.