ABSTRACT: Importance:Long-term adverse health outcomes, particularly those associated with repetitive head impacts, are of growing concern among US-style football players in the US and Canada. Objective:To assess whether exposure to repetitive head impacts during a professional football career is associated with an increase in the risk of all-cause mortality. Design, Setting, and Participants:This retrospective cohort study included 13?912 players in the 1969 to 2017 National Football League (NFL) seasons. All cause-mortality up until July 1, 2018, was included. Data collection was performed from July 13, 2017, to July 1, 2018, as reported in the Pro Football Reference. Exposures:The main exposure was a professional football cumulative head impact index (pfCHII). The pfCHII was measured by combining cumulative padded practice time and games played summed during seasons of play reported in the Pro Football Reference and a player position risk adjustment from helmet accelerometer studies. Main Outcomes and Measures:Demographic characteristics except for the pfCHII were calculated for 14?366 players with complete follow-up. The pfCHII was calculated for 13?912 players (eliminating the 454 specials teams players). Cox proportional hazards regression was used to compare hazard ratios (HRs) of death by repetitive head impacts. Analyses were unadjusted and adjusted for birth year, body mass index, and height. Results:Among 14?366 NFL players who had follow-up for analysis, the mean (SD) age was 47.3 (14.8) years, the mean (SD) body mass index was 29.6 (3.9), and 763 of 14?366 players (5.3%) had died. Among 13?912 players in the pfCHII analysis, the median pfCHII was 32.63 (interquartile range, 13.71-66.12). A 1-log increase in pfCHII was significantly associated with an increased hazard of death for the 1969 to 2017 seasons (HR, 2.02; 95% CI, 1.21-3.37; P?=?.01) after adjustment. The quadratic pfCHII was also statistically significant (HR, 0.91; 95% CI, 0.85-0.98; P?=?.01), indicating that the hazard of death increased at a decreasing rate, whereas the pfCHII increased. Conclusions and Relevance:The findings suggest that an increase in repetitive head impacts is associated with an increased hazard of death among NFL players. Reduction in repetitive head impacts from playing football or other activities through additional rule and equipment changes may be associated with reduced mortality.