Context: While 55 million Americans incorporate running into their exercise routines, up to 65% of runners sustain an overuse injury annually. It has been consistently shown that regular physical activity positively impacts quality of life (QOL), an essential public health indicator; however, the impact of running-related injuries on QOL is unknown. This study seeks to determine whether overuse injury severity impacts QOL in recreational runners, and if self-efficacy mediates this relationship. Design: Community-based prospective cohort study of 300 runners who had been running injury free for at least 5 miles/wk in the past 6 months. Methods: Self-efficacy for running and QOL measures (Short Form-12 Physical Component and Mental Component, Satisfaction with Life, Positive Affect and Negative Affect) were assessed at baseline, time of injury, and follow-up visits. Over 2 years of observation, overuse injuries were diagnosed by an orthopedic surgeon and injured runners were referred to a physical therapist. Results: Injury severity was significantly (P < .01) related with 2 indices of QOL, such that the effect of injury severity was −2.28 units on the Short Form-12 physical component and −0.73 units on positive affect. Self-efficacy accounted for 19% and 48% of the indirect effects on Short Form-12 physical component and positive affect, respectively. Conclusions: Since self-efficacy is a modifiable factor related to decreased QOL, these findings have important clinical implications for rehabilitation interventions.