In this study, the incidence and the sex-specific predictors of running-related injury (RRI) among a group of recreational runners training for a 4-mile running event were determined and identified, respectively. Prospective cohort study. Several potential risk factors were prospectively measured in 629 novice and recreational runners. They were observed during an 8-week training period for any running-related musculoskeletal injuries of the lower limbs and back. A running-related injury was defined as any musculoskeletal pain of the lower limb or back causing a restriction of running for at least 1 day. At least one RRI was reported by 25.9% of the runners during the 8-week observation period. The incidence of RRI was 30.1 (95% CI 25.4 to 34.7) per 1000 h of running exposure. Multivariate Cox regression showed that male participants were more prone to sustain a RRI than female participants (HR 1.4; 95% CI 1.0 to 2.0). No previous running experience was the most important risk factor in male (HR 2.6; 95% CI 1.2 to 5.5) and female (HR 2.1; 95% CI 1.2 to 3.7) participants. The incidence of running-related injuries in recreational runners preparing for a 4-mile running event is substantially high. Male and female participants have different risk profiles. Furthermore, the findings suggest that novice runners may benefit the most out of preventive interventions for RRI.