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Context: A variety of approaches have been proposed to prevent lower limb injuries in runners. However, the evidence for the effectiveness of interventions to reduce lower limb pain and injury after intensive running is very weak. Objective: The authors performed a systematic review to investigate the effects of foot orthoses on pain and the prevention of lower limb injuries in runners. Evidence Acquisition: The authors searched the MEDLINE/PubMed, Physiotherapy Evidence Database, Scielo, and Cochrane Central (from inception to February 2022) databases for randomized controlled trials that evaluated the effects of foot orthoses in runners. The authors then calculated mean differences and 95% confidence intervals from these trials. Heterogeneity was assessed using the I2 test. Furthermore, the authors compared the criteria between runners with foot orthoses and ones with no intervention (control group). Evidence Synthesis: Twelve studies (5321 runners) met our review criteria. The control and the foot orthoses group sustained 721 (37%) and 238 (24%) injuries, respectively. Compared with the control group, the use of foot orthoses resulted in a significant reduction in lower limb injury risk (risk ratio = 0.6; 95% confidence interval, 0.5–0.7; P = .00001, I2 = 54%; 7 studies, N = 2983: moderate-quality evidence). Moreover, the foot orthoses group corresponded to a 40% reduction in the risk of developing lower limb injuries. Conclusions: The use of foot orthoses may help reduce the incidence of lower limb injuries and pain in runners.