Background: Rupture of the anterior cruciate ligament (ACL) is a common and potentially career-threatening injury in the National Football League (NFL). The return to play (RTP) percentage and the factors affecting RTP after ACL reconstruction in NFL players are not well defined. Purpose: To determine the actual rate of return to professional football play in the NFL after ACL reconstruction surgery and to determine what factors can predict ability to RTP. We hypothesize that the RTP percentage in this unique patient population will differ from previously reported populations. Study Design: Case series; Level of evidence, 4. Methods: Forty-nine NFL athletes who had undergone primary ACL reconstruction at our institution were followed to determine their RTP percentages and factors predicting RTP. Results: Sixty-three percent (31 of 49) of NFL athletes returned to NFL game play at an average of 10.8 months after surgery. Age at time of surgery, position, and the type and number of procedures were not significantly different between those who did and did not return to play. The average number of games before surgery was 51 for those who did return to play and 28 for those who did not (P =.039). The odds ratio favoring RTP was 5.5 (P =.016) for those players who had more than 4 years of NFL experience before surgery. The average NFL draft round was 3.4 for the group who returned to play and 6.4 for those who did not (P <.001). The odds ratio favoring RTP was 12.2 (P <.001) for those players drafted in the first 4 rounds of the NFL draft compared with those drafted after the fourth round. Conclusions: The RTP rates after ACL reconstruction in NFL football players are lower than previously perceived. More experienced and established athletes are more likely to return to competition at the same level after this procedure than those with less professional experience. Being selected in the first 4 rounds of the NFL draft was highly predictive of RTP. © 2010 The Author(s).