Background: Minimalist shoes have been popularized as a safe alternative to conventional running shoes. However, a paucity of research is available investigating the longer-term safety of minimalist shoes. Purpose: To compare running-related pain and injury between minimalist and conventional shoes in trained runners and to investigate interactions between shoe type, body mass, and weekly training distance. Study Design: Randomized clinical trial; Level of evidence, 2. Methods: Sixty-one trained, habitual rearfoot footfall runners (mean ± SD: body mass, 74.6 ± 9.3 kg; weekly training distance, 25 ± 14 km) were randomly allocated to either minimalist or conventional shoes. Runners gradually increased the time spent running in their allocated shoes over 26 weeks. Running-related pain intensity was measured weekly by use of 100-mm visual analog scales. Time to first running-related injury was also assessed. Results: Interactions were found between shoe type and weekly training distance for weekly running-related pain; greater pain was experienced with minimalist shoes (P <.05), and clinically meaningful increases (>10 mm) were noted when the weekly training distance was more than 35 km/wk. Eleven of 30 runners sustained an injury in conventional shoes compared with 16 of 31 runners in minimalist shoes (hazard ratio, 1.64; 95% confidence interval, 0.63-4.27; P =.31). A shoe × body mass interaction was found for time to first running-related injury (P =.01). For runners using minimalist shoes, relative to runners using conventional shoes, the risk of sustaining an injury became more likely with increasing body mass above 71.4 kg, and the risk was moderately increased (hazard ratio, 2.00; 95% confidence interval, 1.10-3.66; P =.02) for runners using minimalist shoes who had a body mass of 85.7 kg. Conclusions: Runners should limit weekly training distance in minimalist shoes to avoid running-related pain. Heavier runners are at greater risk of injury when running in minimalist shoes. Registration: Australian New Zealand Clinical Trials Registry (ACTRN12613000642785).