This study was designed to evaluate the efficacy of the HealthWise South Africa HIV and substance abuse prevention program at impacting adolescents' polydrug use and sexual risk behaviors. HealthWise is a school-based intervention designed to promote social-emotional skills, increase knowledge and refusal skills relevant to substance use and sexual behaviors, and encourage healthy free time activities. Four intervention schools in one township near Cape Town, South Africa were matched to five comparison schools (N = 4040). The sample included equal numbers of male and female participants (Mean age = 14.0). Multiple regression was used to assess the impact of HealthWise on the outcomes of interest. Findings suggest that among virgins at baseline (beginning of eighth grade) who had sex by Wave 5 (beginning of 10th grade), HealthWise youth were less likely than comparison youth to engage in two or more risk behaviors at last sex. Additionally, HealthWise was effective at slowing the onset of frequent polydrug use among non-users at baseline and slowing the increase in this outcome among all participants. Program effects were not found for lifetime sexual activity, condomless sex refusal and past-month polydrug use. These findings suggest that HealthWise is a promising approach to HIV and substance abuse prevention.