BACKGROUND: Over 7 million students participate in high school athletics annually. Despite numerous health benefits, high school athletes are at risk for injury. HYPOTHESIS: Severe injury rates and patterns differ by gender and type of exposure. Study Design Descriptive epidemiology study. METHODS: Sports-related injury data were collected during the 2005-2007 academic years from 100 nationally representative United States high schools via RIO (Reporting Information Online). Severe injury was defined as any injury that resulted in the loss of more than 21 days of sports participation. RESULTS: Participating certified athletic trainers (ATCs) reported 1378 severe injuries during 3 550 141 athlete-exposures (0.39 severe injuries per 1000 athletic exposures). Football had the highest severe injury rate (0.69), followed by wrestling (0.52), girls' basketball (0.34), and girls' soccer (0.33). The rate in all boys' sports (0.45) was higher than all girls' sports (0.26) (rate ratio [RR], 1.74; 95% confidence interval [CI], 1.54-1.98; P < .001). However, among directly comparable sports (soccer, basketball, and baseball/softball), girls sustained a higher severe injury rate (0.29) than boys (0.23) (RR, 1.28; 95% CI, 1.08-1.52; P = .006). More specifically, girls' basketball had a higher rate (0.34) than boys' basketball (0.24) (RR, 1.43; 95% CI, 1.10-1.86; P = .009). Differences between boys' and girls' soccer and baseball/softball were not statistically significant. The severe injury rate was greater in competition (0.79) than practice (0.24) (RR, 3.30; 95% CI, 2.97-3.67; P < .001). Nationally, high school athletes sustained an estimated 446 715 severe injuries from 2005-2007. The most commonly injured body sites were the knee (29.0%), ankle (12.3%), and shoulder (10.9%). The most common diagnoses were fractures (36.0%), complete ligament sprains (15.3%), and incomplete ligament sprains (14.3%). Of severe sports injuries, 0.3% resulted in medical disqualification for the athletes' career, and an additional 56.8% resulted in medical disqualification for the entire season. One in 4 (28.3%) severe injuries required surgery, with over half (53.9%) being knee surgeries. CONCLUSION: Severe injury rates and patterns varied by sport, gender, and type of exposure. Because severe injuries negatively affect athletes' health and often place an increased burden on the health care system, future research should focus on developing interventions to decrease the incidence and severity of sports-related injuries.