This original prospective cohort study was conducted in an attempt to significantly reduce the incidence and the severity of injuries in an intervention cohort as compared to a two-season historical cohort, and to provide recommendations to the International Federation of Football (IFAF) pertaining to prevention measures to make the game safer. A total of 1,260 amateur male (mean age: 20.4 +/- 3.9 years) and 244 female (mean age: 18.5 +/- 1.7 years) players participated in the study. Four prevention measures were implemented: the no-pocket rule, self-fitting mouth guards, ankle braces (for those players with recurrent ankle sprains) and an injury treatment information brochure. All time-loss injuries sustained in game sessions were recorded by the off-the-field medical personnel and followed up by a more detailed phone injury surveillance questionnaire. There was a 54 % reduction in the total number of injuries and a significant reduction in the incidence rate and incidence proportion between the intervention cohorts as compared to the historical cohort (p < 0.001). There was no statistically significant reduction in the number of injuries in any of the body parts, except for in hand/wrist injuries related to the use of pockets (p < 0.001), as well as the severity of mild-moderate injuries (p < 0.05). This study provided evidence that hand/wrist injuries can be significantly reduced in flag football. Recommendations to the IFAF include strict enforcement of the no-pocket rule, the use of soft headgear, comfortable-fitting ankle braces and mouth guards and additionally, to change game rules concerning blocking. II.