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).Prospective cohort study with a 9-month follow-up.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 ≥2 h) and session frequency (dichotomized into <2 and ≥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.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).The effect of a runner's training load on running-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.