An overlooked sequela of HIV risk is trauma exposure, yet few HIV interventions address trauma exposure, mental health, and substance misuse. In a two-arm randomized controlled trial 73 Native American women were randomized to a culturally-adapted Cognitive Processing Therapy (CPT) or 6-weeks waitlist. Outcomes assessed: PTSD symptom severity, alcohol use frequency, substance abuse or dependence diagnosis, and high-risk sexual behavior defined as vaginal/anal intercourse (a) under the influence of alcohol and/or illicit substances, (b) with a partner who was concurrently sexually active with someone else, and/or (c) with more than one partner in the past 6 weeks. Among immediate intervention participants, compared to waitlist participants, there were large reductions in PTSD symptom severity, high-risk sexual behavior, and a medium-to-large reduction in the frequency of alcohol use. CPT appears to improve mental health and risk behaviors, suggesting that addressing PTSD may be one way of improving HIV-risk related outcomes.