BACKGROUND: Complex regional pain syndrome (CRPS) is characterized by severe pain accompanied by vascular, motor, or trophic changes. Targeted muscle reinnervation (TMR) has been shown to improve phantom limb pain in lower extremity (LE) amputation. The objective of this case series was to characterize TMR as a treatment for CRPS patients with LE amputation. METHODS: A retrospective review was done of CRPS patients receiving LE amputation and TMR with a single surgeon from 2018-2021. Demographics, operative details, and pain outcomes were collected. Variables were analyzed using appropriate statistical tests. RESULTS: There were 6 patients identified, all Caucasian women, with an average age of 32.5±15.4 years and body mass index (BMI) 24.9±5.0 kg/m2. CRPS was the indication for all amputations, done either before or during TMR. All patients were following with Pain Management at the time of TMR. Patients 1 and 2 both carried a CRPS diagnosis due to LE trauma less than 1 year before TMR, for 4 and 11 months respectively. Patient 1 had a simultaneous amputation with TMR, while patient 2 had an amputation 11 months prior. Both patients were otherwise healthy and previously tried ketamine infusions to control their CRPS. They were followed for an average of 11±4.2 months after TMR procedure, and reported no change in their pain based on NRS pain assessments. Patient 1 did not have any previous nerve operations, while Patient 2 had a tibial nerve coaptation and saphenous neurectomy during amputation. At most recent follow up, Patient 1 reported complete resolution of pain and a decreased dose of their neuroleptic medication. Patient 2 continued to endorse generalized pain, but denied any resting leg pain (RLP) or phantom limb pain (PLP). Both Patients 1 and 2 were newly independently ambulatory 90 and 122 days after TMR, respectively, reporting the improvement in pain quality allowed them to tolerate a prosthetic. The remaining four patients all carried a CRPS diagnosis due to trauma or a post-surgical etiology ranging from 3-8 years before TMR. They were all otherwise healthy, with exception of a Sjogren’s (patient 3) and an Ehlers Danlos diagnosis (patient 4). Both of these patients had simultaneous amputation and TMR. Patients 5 and 6 had amputations beforehand, waiting 16 and 93 months, respectively. All had tried either ketamine infusions, spinal cord stimulation, DRG stimulation, or lumbar nerve blocks before TMR. When comparing pre- and post- TMR NRS values, all reported a 2-point increase with exception of patient 5, who maintained a score of 7 both before and after TMR. At most recent follow up, all patients endorsed generalized pain. All but patient 6 continued to endorse PLP after TMR. Of note, patient 6 had multiple neuroma excisions before TMR and reported a decrease in their narcotic dosage by most recent follow up. There were no changes between pre- and post- TMR ambulation status for these patients. CONCLUSION: CRPS is a debilitating condition with a variety of treatment options. Operative results may be improved for patients who have TMR done earlier after CRPS diagnosis.