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South Africa's concurrent epidemics of HIV, substance use, and gender-based violence point to the urgent need for interventions that address the intersectional nature of these issues. A community-based randomized trial assessed the efficacy of an adapted evidence-based Woman-Focused HIV intervention addressing all three issues with sex workers and non-sex workers. At 6-month follow-up, non-sex workers in the Woman-Focused intervention reported significantly lower mean numbers of days drinking alcohol in the previous 30 days, were significantly less likely to meet DSM-IV criteria for alcohol dependence, were more likely to report using a condom at last sex with a main partner, and were less likely to report sexual abuse by a main partner in the previous 90 days. Sex workers in the Woman-Focused intervention were significantly less likely to report physical abuse by a main partner. The findings suggest that gender-focused interventions can be effective for vulnerable women and should be offered more broadly.