The aim of this study was to determine if runners who use concomitantly different pairs of running shoes are at a lower risk of running-related injury (RRI). Recreational runners (n = 264) participated in this 22-week prospective follow-up and reported all information about their running session characteristics, other sport participation and injuries on a dedicated Internet platform. A RRI was defined as a physical pain or complaint located at the lower limbs or lower back region, sustained during or as a result of running practice and impeding planned running activity for at least 1 day. One-third of the participants (n = 87) experienced at least one RRI during the observation period. The adjusted Cox regression analysis revealed that the parallel use of more than one pair of running shoes was a protective factor [hazard ratio (HR) = 0.614; 95% confidence interval (CI) = 0.389–0.969], while previous injury was a risk factor (HR = 1.722; 95%CI = 1.114–2.661). Additionally, increased mean session distance (km; HR = 0.795; 95%CI = 0.725–0.872) and increased weekly volume of other sports (h/week; HR = 0.848; 95%CI = 0.732–0.982) were associated with lower RRI risk. Multiple shoe use and participation in other sports are strategies potentially leading to a variation of the load applied to the musculoskeletal system. They could be advised to recreational runners to prevent RRI.