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Background: American football and rugby players are at substantial risk of injury because of the full-contact nature of these sports. Methodological differences between previous epidemiological studies hamper an accurate comparison of injury rates between American football and rugby. Purpose: To directly compare injury rates in American collegiate football and rugby, specified by location, type, mechanism, and severity of injury, as reported by licensed medical professionals. Study Design: Cohort study; Level of evidence, 2. Methods: Licensed medical professionals (athletic trainer or physician) associated with the football and rugby teams of a National Collegiate Athletic Association Division I university reported attendance and injury details over 3 autumn seasons. Injuries were categorized by the location, type, mechanism, and severity of injury, and the injury rate was calculated per 1000 athlete-exposures (AEs). Injury rate ratios (IRRs) were calculated to compare overall, game, and practice injury rates within and between sports. Results: The overall injury rate was 4.9/1000 AEs in football versus 15.2/1000 AEs in rugby: IRR = 3.1 (95% CI, 2.3-4.2). Game injury rates were higher than practice injury rates: IRR = 6.5 (95% CI, 4.5-9.3) in football and IRR = 5.1 (95% CI, 3.0-8.6) in rugby. Injury rates for the shoulder, wrist/hand, and lower leg and for sprains, fractures, and contusions in rugby were >4 times as high as those in football (all P ≤ 0.006). Concussion rates were 1.0/1000 AEs in football versus 2.5/1000 AEs in rugby. Most injuries occurred via direct player contact, especially during games. The rate of season-ending injuries (>3 months of time loss) was 0.8/1000 AEs in football versus 1.0/1000 AEs in rugby: IRR = 1.3 (95% CI, 0.4-3.4). Conclusion: Overall injury rates were substantially higher in collegiate rugby compared with football. Similarities between sports were observed in the most common injury types (sprains and concussions), locations (lower extremity and head), and mechanisms (direct player contact). Upper extremity injuries were more common in rugby, and the rate of season-ending injuries was similar between sports. [ABSTRACT FROM AUTHOR]