Background:Anterior cruciate ligament (ACL) injuries are common in American football players. The risk of subsequent ACL reinjury to either the ipsilateral or the contralateral knee in National Football League (NFL) draftees with a history of successful ACL reconstruction before entering the NFL remains unknown.Hypothesis:NFL athletes with a history of successful ACL reconstruction before being drafted will likely demonstrate increased risk of subsequent ACL injury when compared with a control cohort consisting of players of similar positions and draft class.Study Design:Cohort study; Level of evidence, 3.Methods:Detailed orthopaedic evaluations of NFL Combine participants from 2006 to 2012 were obtained to identify players entering the NFL draft with a history of successful ACL reconstruction. A control cohort was created in a 2:1 ratio, consisting of players matched by position and draft class.Results:Of the 2016 players invited to the NFL Combine during the study period, 100 met the inclusion criteria. A total of 26 subsequent ACL reinjuries (12 ipsilateral, 14 contralateral) occurred in 25 players (25%) while playing in the NFL, with injuries occurring at a mean of 22.1 months after the NFL draft. In comparison, 18 of the 200 (9%) carefully matched cohort players without history of prior ACL injury sustained a new ACL injury during this time period (P < .001).Conclusion:NFL athletes with a history of successful ACL reconstruction before being drafted into the NFL have a significantly higher rate of subsequent ACL reinjury while playing in the NFL when compared with a carefully matched cohort of players without a history of prior ACL injury.