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A better understanding of the factors influencing return to work (RTW) after major limb trauma is essential in reducing the high costs associated with these injuries.Patients (n = 423) who underwent amputation or reconstruction after limb threatening lower extremity trauma and who were working before the injury were prospectively evaluated at 3, 6, 12, 24, and 84 months. Time to first RTW was assessed. For individuals working at 84 months, the percentage of time limited in performance at work was estimated using the Work Limitations Questionnaire.Estimates of the cumulative proportion returning to work at 3, 6, 12, 24, and 84 months were 0.12, 0.28, 0.42, 0.51, and 0.58. Patients working at 84 months were, on average, limited in their ability to perform the demands of their job 20 to 25% of the time. In the context of a Cox proportional hazards model, differences in RTW outcomes by treatment (amputation versus reconstruction) were not statistically significant. Factors that were significantly associated (p < 0.05) with higher rates of RTW include younger age, being White, higher education, being a nonsmoker, average to high self efficacy, preinjury job tenure, higher job involvement, and no litigation. Early (3 month) assessments of pain and physical functioning were significant predictors of RTW.Return to work after severe lower extremity trauma remains a challenge. Although the causal pathway from injury to impairment and work disability is complex, this study points to several factors that influence RTW that suggest strategies for intervention.