BACKGROUND: Ankle sprains are the most common musculoskeletal injuries that occur in athletes, and they have a profound impact on health care costs and resources. HYPOTHESIS: A balance training program can reduce the risk of ankle sprains in high school athletes. STUDY DESIGN: Randomized controlled clinical trial; Level of evidence, 1. METHODS: Seven hundred and sixty-five high school soccer and basketball players (523 girls and 242 boys) were randomly assigned to either an intervention group (27 teams, 373 subjects) that participated in a balance training program or to a control group (28 teams, 392 subjects) that performed only standard conditioning exercises. On-site athletic trainers recorded athlete exposures and sprains. RESULTS: The rate of ankle sprains was significantly lower for subjects in the intervention group (6.1%, 1.13 of 1000 exposures vs 9.9%, 1.87 of 1000 exposures; P = .04). Athletes with a history of an ankle sprain had a 2-fold increased risk of sustaining a sprain (risk ratio, 2.14), whereas athletes who performed the intervention program decreased their risk of a sprain by one half (risk ratio, 0.56). The ankle sprain rate for athletes without previous sprains was 4.3% in the intervention group and 7.7% in the control group, but this difference was not significant (P = .059). CONCLUSION: A balance training program will significantly reduce the risk of ankle sprains in high school soccer and basketball players.