Background:At the annual National Football League (NFL) Scouting Combine, the medical staff of each NFL franchise performs a comprehensive medical evaluation of all athletes potentially entering the NFL. Currently, little is known regarding the overall epidemiology of injuries identified at the combine and their impact on NFL performance.Purpose:To determine the epidemiology of injuries identified at the combine and their impact on initial NFL performance.Study Design:Cohort study; Level of evidence, 3.Methods:All previous musculoskeletal injuries identified at the NFL Combine from 2009 to 2015 were retrospectively reviewed. Medical records and imaging reports were examined. Game statistics for the first 2 seasons of NFL play were obtained for all players from 2009 to 2013. Analysis of injury prevalence and overall impact on the draft status and position-specific performance metrics of each injury was performed and compared with a position-matched control group with no history of injury or surgery.Results:A total of 2203 athletes over 7 years were evaluated, including 1490 (67.6%) drafted athletes and 1040 (47.2%) who ultimately played at least 2 years in the NFL. The most common sites of injury were the ankle (1160, 52.7%), shoulder (1143, 51.9%), knee (1128, 51.2%), spine (785, 35.6%), and hand (739, 33.5%). Odds ratios (ORs) demonstrated that quarterbacks were most at risk of shoulder injury (OR, 2.78; P = .001), while running backs most commonly sustained ankle (OR, 1.39; P = .040) and shoulder injuries (OR, 1.55; P = .020) when compared with all other players. Ultimately, defensive players demonstrated a greater negative impact due to injury than offensive players, with multiple performance metrics significantly affected for each defensive position analyzed, whereas skilled offensive players (eg, quarterbacks, running backs) demonstrated only 1 metric significantly affected at each position.Conclusion:The most common sites of injury identified at the combine were (1) ankle, (2) shoulder, (3) knee, (4) spine, and (5) hand. Overall, performance in the NFL tended to worsen with injury history, with a direct correlation found between injury at a certain anatomic location and position of play. Defensive players tended to perform worse compared with offensive players if injury history was present.