AbstractYoung men in South Africa face the intersecting epidemics of HIV, substance use and endemic poverty. We tested the effectiveness of a behavioral intervention using soccer training to reduce the cluster of risks associated with HIV and substance use. This cluster randomized controlled trial was conducted with men aged 18–29 years old in 27 neighborhoods in the townships of Cape Town, South Africa. Neighborhoods were randomized to receive for 6 months either: (1) Soccer League (SL; n = 18 neighborhoods, n = 778 men) who attended soccer three times weekly (72 sessions; 94% uptake, 45.5% weekly attendance rate), combined with an HIV/substance use, cognitive-behavioral intervention; or (2) a Control Condition (CC; n = 9; 415 men) who received educational materials and referrals at 3 month intervals. The primary outcome was the number of significant changes in a cluster of outcomes including HIV-related risks, substance abuse, employment/income, mental health, violence, and community engagement. There was only one significant difference on the rapid diagnostic tests for mandrax at 6 months, an insufficient number of changes to indicate a successful intervention. A group-based behavioral intervention was ineffective in addressing multiple risk behaviors among at-risk young men, similar to the findings of several recent soccer-related interventions. Early adulthood may be too late to alter well-established patterns of risk behaviors.Clinical Trial Registration This trial was prospectively registered on 24 November 2014 with ClinicalTrials.gov NCT02358226.