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Ankle sprain is a common injury in athletic populations that results in significant time lost to injury.The incidence rates (IRs) of ankle ligament sprains are influenced by gender, height, weight, body mass index (BMI), physical conditioning, level of competition, type of sport, and athlete exposure to sport.Cohort study; Level of evidence, 2.A longitudinal cohort study was performed to determine the effect of risk factors for ankle sprain at the United States Military Academy between 2005 and 2007.A total 614 cadets sustained new ankle sprains during 10 511 person-years at risk, resulting in an overall IR of 58.4 per 1000 person-years. Women (96.4), compared with men (52.7), had a significantly increased rate ratio (IRR) for ankle sprain of 1.83 (95% confidence interval [CI], 1.52-2.20). Men with ankle sprains had higher mean height, weight, and BMI than uninjured men (P < .001). Men with ankle sprains had higher average scores in push-ups, sit-ups, and run time than uninjured men (P < .001). Ankle sprain occurred most commonly during athletics (64.1%). Ankle sprain IR did not significantly differ between intercollegiate and intramural athletic competition after controlling for athlete-exposure (IRR, 1.05; 95% CI, 0.81-1.37). The ankle sprain IRR of female compared with male intercollegiate athletes was 0.93 (95% CI, 0.67-1.32) per 1000 person-years and 1.04 (95% CI, 0.74-1.47) per 1000 athlete-exposures. The intercollegiate sports of men's rugby, women's cheerleading, and men's/women's basketball, soccer, and lacrosse had the highest ankle sprain IR.Higher mean height and weight in men, increased BMI in men, greater physical conditioning in men, and athlete exposure to selected sports were all risk factors for ankle sprain.