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U.S. high school athletes sustain millions of injuries annually. Detailed patterns of knee injuries, among the most costly sports injuries, remain largely unknown. We hypothesize that patterns of knee injuries in U.S. high school sports differ by sport and sex.U.S. high school sports-related injury data were collected for 20 sports using the National High School Sports-Related Injury Surveillance System, High School RIO™. Knee injury rates, rate ratios (RR), and injury proportion ratios were calculated.From 2005/2006 to 2010/2011, 5116 knee injuries occurred during 17,172,376 athlete exposures (AE) for an overall rate of 2.98 knee injuries per 10,000 AE. Knee injuries were more common in competition than in practice (rate ratio = 3.53, 95% confidence interval [CI] = 3.34–3.73). Football had the highest knee injury rate (6.29 per 10,000 AE) followed by girls’ soccer (4.53) and girls’ gymnastics (4.23). Girls had significantly higher knee injury rates than boys in sex-comparable sports (soccer, volleyball, basketball, baseball/softball, lacrosse, swimming and diving, and track and field; RR = 1.52, 95% CI = 1.39–1.65). The most commonly involved structure was the medial collateral ligament (reported in 36.1% of knee injuries), followed by the patella/patellar tendon (29.5%), anterior cruciate ligament (25.4%), meniscus (23.0%), lateral collateral ligament (7.9%), and posterior cruciate ligament (2.4%). Girls were significantly more likely to sustain anterior cruciate ligament injuries in sex-comparable sports (RR = 2.38, 95% CI = 1.91–2.95). Overall, 21.2% of knee injuries were treated with surgery; girls were more often treated with surgery than boys in sex-comparable sports (injury proportion ratio = 1.30, 95% CI = 1.11–1.53).Knee injury patterns differ by sport and sex. Continuing efforts to develop preventive interventions could reduce the burden of these injuries.