Objectives: To investigate the association between training-related characteristics and running-related injury using a new conceptual model for running-related injury generation, focusing on the synergy between training load and previous injuries, short-term running experience or body mass index (>or <25 kg m(-2)). Design: Prospective cohort study with a 9-month follow-up. Methods: The data of two previous studies using the same methodology were revisited. Recreational runners (n = 517) reported information about running training characteristics (weekly distance, frequency, speed), other sport participation and injuries On a dedicated internet platform. Weekly volume (dichotomized into= 2 h) and session frequency (dichotomized into= 2) were the main exposures because they were considered necessary causes for running-related injury. Non-training-related characteristics were included in Cox regression analyses as effect-measure modifiers. Hazard ratio was the measure of association. The size of effect-measure modification was calculated as the relative excess risk due to interaction. Results: One hundred sixty-seven runners reported a running-related injury. Crude analyses revealed that weekly volume <2 h (hazard ratio =3.29; 95% confidence intervals = 2.27; 4.79) and weekly session frequency <2 (hazard ratio =2.41; 95% confidence intervals =1.71; 3.42) were associated with increased injury rate. Previous injury was identified as an effect-measure modifier on weekly volume (relative excess risk due to interaction = 4.69; 95% confidence intervals = 1.42; 7.95; p = 0.005) and session frequency (relative excess risk due to interaction = 2.44; 95% confidence intervals = 0.48; 4.39; p = 0.015). A negative synergy was found between body mass index and weekly volume (relative excess risk due to interaction = -2.88; 95% confidence intervals = -5.10; -0.66; p = 0.018). Conclusions: The effect of a runner's training load on rurining-related injury is influenced by body mass index and previous injury. These results show the importance to distinguish between confounding and effect-measure modification in running-related injury research. (C) 2014 Sports Medicine Australia. Published by Elsevier Ltd.