Background <p>Post-mastectomy pain syndrome (PMPS) is a common issue impacting many patients undergoing mastectomy for treatment of breast cancer. Neuroma formation has been identified as a major cause of PMPS secondary to injury of intercostal nerves during mastectomy. Historically, neuromas of the chest wall have been treated with surgical implantation into surrounding tissues. Targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI) have been used to great effect in treatment of neuromas of the extremities. It is our hypothesis that RPNI would be an effective treatment modality for neuroma prevention in post mastectomy patients.</p> Methods <p>A retrospective review of patients undergoing immediate implant based breast reconstruction following mastectomy at one institution was conducted. All patients undergoing RPNI to a transected intercostal nerve were included. Data collected included follow up time, oncologic treatment, patient incidence of post mastectomy pain, and short-form McGill pain questionnaire 2 (SF-MPQ-2) results.</p> Results <p>Ten patients were included in our cohort. Average follow up time after mastectomy and RPNI was 6.9 months. RPNI was performed on 1.4 nerves per patient in this study. There were no cases of clinical PMPS in our cohort. McGill pain questionnaire administered indicated rating of 2.33 out of ten for neuropathic descriptors and 2.08 out of 10 for all pain indicators at final follow up.</p> Conclusions <p>Our findings suggest RPNI could be a powerful tool for the prevention of pain in breast cancer patients following mastectomy. Future study is needed in treatment of diagnosed PMPS with the use of the RPNI technique. Level of Evidence: Level IV, risk / prognostic.</p>