Background:Originally designed for prosthetic control, regenerative peripheral nerve interfaces (RPNIs) prevent neuroma formation by providing free muscle grafts as physiological targets for peripheral nerve ingrowth. We report the first series of patients undergoing RPNI implantation for treatment of symptomatic postamputation neuromas.Methods:A retrospective case series of all amputees undergoing RPNI implantation for treatment of symptomatic neuromas between November 2013 and June 2015 is presented. Data were obtained via chart review and phone interviews using questions derived from the Patient Reported Outcomes Measurement Information System instruments. Statistical analyses were performed using dependent sample t tests with a significance threshold of P < 0.01.Results:Forty-six RPNIs were implanted into 16 amputees for neuroma relief (3 upper extremities and 14 lower extremities). Mean age was 53.5 years (6 females and 10 males). All patients participated in postoperative phone interviews at 7.5 ± 3.4 (range: 3–15) months. Patients reported a 71% reduction in neuroma pain and a 53% reduction in phantom pain. Most patients felt satisfied or highly satisfied with RPNI surgery (75%), reporting decreased (56%) or stable (44%) levels of analgesic use. Most patients would strongly recommend RPNI surgery to a friend (88%) and would do it again if given the option (94%). Complications included delayed wound healing (n = 4) and neuroma pain at a different site (n = 2).Conclusions:RPNI implantation carries a reasonable complication profile while offering a simple, effective treatment for symptomatic neuromas. Most patients report a significant reduction in neuroma and phantom pain with a high level of satisfaction. The physiological basis for preventing neuroma recurrence is an intriguing benefit to this approach.