Sports-related injuries are an issue of concern in high school sports athletes. A prospective cohort study of injury risk factors was conducted from 1996 to 1999 among varsity high school athletes in 12 sports in 100 North Carolina high schools. Data were collected by trained school personnel. Unadjusted and adjusted incidence rates and rate ratios were estimated using Poisson regression models. The overall rate of injury was 2.08 per 1,000 athlete-exposures (95% confidence interval (CI):​ 1.79, 2.41). At 3.54 per 1,000 athlete-exposures (95% CI:​ 2.87, 4.37), football had the highest rate of injury of all sports. The adjusted rate ratio for athletes with a history of injury, compared with those without a prior injury, was 1.94 (95% CI:​ 1.69, 2.22). The injury rate rose with each year of playing experience (rate ratio = 1.06, 95% CI:​ 1.01, 1.12). In a subanalysis restricted to gender-comparable sports, boys had a higher rate of injury than did girls (rate ratio = 1.33, 95% CI:​ 0.99, 1.79). All other factors did not appear to be independent predictors of the injury rate. The influence of prior injury suggests that proper rehabilitation and primary prevention of the initial injury are important strategies for injury control.