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Nipple-sparing mastectomy with immediate prosthetic reconstruction is routinely performed because of excellent aesthetic results and safe oncologic outcomes. Typically, subpectoral expanders are placed, but in select patients, this can lead to significant postoperative pain and animation deformity, caused by pectoralis major muscle disinsertion and stretch. Prepectoral reconstruction is a technique that eliminates dissection of the pectoralis major by placing the prosthesis completely above the muscle with complete acellular dermal matrix coverage.A single surgeon’s experience with immediate prosthetic reconstruction following nipple-sparing mastectomy from 2012 to 2016 was reviewed. Patient demographics, adjuvant treatment, length and characteristics of the expansion, and incidence of complications during the tissue expander stage were compared between the partial submuscular/partial acellular dermal matrix (dual-plane) cohort and the prepectoral cohort.Fifty-one patients (84 breasts) underwent immediate prepectoral tissue expander placement, compared with 115 patients (186 breasts) undergoing immediate partial submuscular expander placement. The groups had similar comorbidities and postoperative radiation exposure. There was no significant difference in overall complication rate between the two groups (17.9 percent versus 18.8 percent; p = 0.49).Prepectoral breast reconstruction provides a safe and effective alternative to partial submuscular reconstruction, that yields comparable aesthetic results with less operative morbidity. In the authors’ experience, the incidence of acute and chronic postoperative pain and animation deformity is significantly lower following prepectoral breast reconstruction. This technique is now considered for all patients who are safe oncologic candidates and are undergoing nipple-sparing mastectomy and prosthetic reconstruction.Therapeutic, III.