The purpose of our study was to investigate the association between prior head injury and the likelihood of being diagnosed with clinical depression among retired professional football players with prior head injury exposure. A general health questionnaire, including information about prior injuries, the SF-36 (Short Form 36), and other markers for depression, was completed by 2552 retired professional football players with an average age of 53.8 (+/-13.4) yr and an average professional football-playing career of 6.6 (+/-3.6) yr. A second questionnaire focusing on mild cognitive impairment (MCI)-related issues was completed by a subset of 758 retired professional football players (50 yr and older). Two hundred sixty-nine (11.1%) of all respondents reported having prior or current diagnosis of clinical depression. There was an association between recurrent concussion and diagnosis of lifetime depression (chi2=71.21, df=2, P<0.005), suggesting that the prevalence increases with increasing concussion history. Compared with retired players with no history of concussion, retired players reporting three or more previous concussions (24.4%) were three times more likely to be diagnosed with depression; those with a history of one or two previous concussions (36.3%) were 1.5 times more likely to be diagnosed with depression. The analyses controlled for age, number of years since retirement, number of years played, physical component score on the SF-36, and diagnosed comorbidities such as osteoarthritis, coronary heart disease, stroke, cancer, and diabetes. Our findings suggest a possible link between recurrent sport-related concussion and increased risk of clinical depression. The findings emphasize the importance of understanding potential neurological consequences of recurrent concussion.