Postmastectomy pain syndrome (PMPS) represents a common complication following breast surgery defined as a chronic neuropathic pain located in the front of the chest, in the axilla and in the upper arm that for more than 3 months after surgery. Several medications prove to be ineffective while autologous fat grafting revealed to be an innovative solution in the treatment of neuropathic pain syndromes based on retrospective studies. For this reason, we performed a prospective multicenter trial to reduce the memory bias and further increase the evidence of the results. From February 2018 to March 2019, 37 female patients aged between 18 and 80 years, underwent mastectomy or quadrantectomy with pathologic scarring and chronic persistent neuropathic pain, compatible with PMPS, are been included in the study and treated with autologous fat grafting. During the enrollment phase, patients were asked to estimate pain using the Visual Analogue Scale (VAS) and POSAS questionnaire in order to evaluate scar outcomes. The VAS scale, starting from 6.9 (1.3), decreased in the first month by 3.10 (1.59), continuing to fall by 0.83 (1.60) to 3 months and by 0.39 (2.09) at 6 months. Statistical analysis showed a significant reduction after 1 month (P < .0001) and 3 months (P < .005). All POSAS grades documented a statistically significant reduction (P < .0001) of the scores by both observers and patients. We observed that no significant association was found between age, BMI, menopausal status of patients, days from oncologic surgery to autologous fat grafting and reduction of VAS values over time while both smoking and axillary dissection were observed as the main factor significantly associated with a reduced clinical efficacy (respectively, P = .0227 and P = .0066). Our prospective multicenter trial confirms the efficacy of fat grafting in the treatment of PMPS based on the principle of regenerative medicine with a satisfactory response in terms of pain reduction and improvement of the quality of the treated tissues. Clinical questionnaires show that the cicatricial areas improve in terms of color, thickness, skin pliability, and surface irregularities. Regenerative effect is based also on the adoption of needles. The combined effect of fat grafting and needles determines a clinical full response.