BACKGROUND: The experience of sexual assault may be associated with numerous adverse outcomes, including depressive disorders and heavy substance use. We aimed to examine the relationship between heavy substance use and depression in victims of sexual assault. METHODS: We used nationally representative data from the German Health and Sexuality Survey (GeSiD) with N = 4,955 women and men aged 18-75 years. We assessed (i) the potential effect of sexual assault experience on depression mediated through hazardous alcohol, heavy tobacco, and frequent cannabis use and (ii) sexual assault experience on heavy substance use mediated through depression using logistic regression analysis to estimate proportion mediated (PM). RESULTS: We found some evidence of mediation between sexual assault as a lifetime event and depression by heavy tobacco use (PM = 1.6%) and frequent cannabis use (PM = 14.7%) among women. We also observed mediation by hazardous alcohol use (PM = 35.5%) and heavy tobacco use (PM = 48.6%) among men who experienced childhood sexual assault. Focusing on depression as a potential mediator, we found some evidence of mediation between sexual assault as a lifetime event and heavy tobacco use among women (PM = 17.6%) and men (PM = 13.3%), and between sexual assault as a lifetime event and frequent cannabis use (PM = 26.9%) among women. CONCLUSIONS: Our findings suggest that public health specialists, clinicians, and therapists should develop early interventions to prevent addiction and the development of depression after experiencing sexual assault.