BACKGROUND: Laboratory-based studies on neuromuscular control after concussion and epidemiological studies suggest that concussion may increase the risk of subsequent musculoskeletal injury. OBJECTIVE: The purpose of this study was to determine if athletes have an increased risk of lower extremity musculoskeletal injury after return to play from a concussion. METHODS: Injury data were collected from 2006 to 2013 for men's football and for women's basketball, soccer and lacrosse at a National Collegiate Athletic Association Division I university. Ninety cases of in-season concussion in 73 athletes (52 male, 21 female) with return to play at least 30 days prior to the end of the season were identified. A period of up to 90 days of in-season competition following return to play was reviewed for time-loss injury. The same period was studied in up to two control athletes who had no concussion within the prior year and were matched for sport, starting status and position. RESULTS: Lower extremity musculoskeletal injuries occurred at a higher rate in the concussed athletes (45/90 or 50 %) than in the non-concussed athletes (30/148 or 20 %; P < 0.01). The odds of sustaining a musculoskeletal injury were 3.39 times higher in the concussed athletes (95 % confidence interval 1.90-6.05; P < 0.01). Overall, the number of days lost because of injury was similar between concussed and non-concussed athletes (median 9 versus 15; P = 0.41). CONCLUSIONS: The results of this study demonstrate a relationship between concussion and an increased risk of lower extremity musculoskeletal injury after return to play, and may have implications for current medical practice standards regarding evaluation and management of concussion injuries.