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Background:. Orthopaedic trauma etiologies are a common cause for amputation. Targeted muscle reinnervation (TMR) is a technique aimed at reducing or preventing pain and improving function. The purpose of this study was to examine postoperative phantom limb pain and residual limb pain following TMR in orthopaedic trauma amputees. In addition, postoperative rates of opioid and neuromodulator medication use were evaluated. Methods:. Twenty-five patients (60% male) prospectively enrolled in a single-institution study and underwent TMR at the time of major limb amputation (48% nonmilitary trauma, 32% infection secondary to previous nonmilitary trauma, and 20% other, also secondary to trauma). Phantom limb pain and residual limb pain scores, pain temporality, prosthetic use, and unemployment status were assessed at the time of follow-up. The use of opioid and neuromodulator medications both preoperatively and postoperatively was also examined. Results:. At a mean follow-up of 14.1 months, phantom limb pain and residual limb pain scores were low, with 92% of the patients reporting no pain or brief intermittent pain only. Pain scores were higher overall for male patients compared with female patients (p < 0.05) except for 1 subscore, and higher in patients who underwent amputation for infection (odds ratio, 9.75; p = 0.01). Sixteen percent of the patients reported opioid medication use at the time of the latest documented follow-up. Fifty percent of the patients who were taking opioids preoperatively discontinued use postoperatively, while 100% of the patients who were not taking opioids preoperatively discontinued postoperative use. None of the patients who were taking neuromodulator medication preoperatively discontinued use postoperatively (0 of 5). The median time to neuromodulator medication discontinuation was 14.6 months, with female patients taking longer than male patients (23 compared with 7 months; p = 0.02). At the time of the latest follow-up, the rate of reported prosthetic use was 85% for lower-extremity and 40% for upper-extremity amputees, with a rate of unemployment due to disability of 36%. Conclusions:. The use of TMR in orthopaedic trauma amputees was associated with low overall pain scores at 2-year follow-up, decreased overall opioid and neuromodulator medication use, and an overall high rate of daily prosthetic use. Level of Evidence:. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.