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Prosthetic breast reconstruction with prepectoral placement may confer clinical advantages compared with subpectoral placement. The purpose of this study was to assess and compare clinical outcomes following 2-stage reconstruction following prepectoral and partial subpectoral placement of tissue expanders and implants.A retrospective review of 39 (prepectoral) and 50 (partial subpectoral) patients was completed. Acellular dermal matrix was used in all patients. Mean age was 50.4 and 49.2 years, respectively. Body mass index (BMI) > 30 was noted in 15.4% of prepectoral and 18% of partial subpectoral patients. Radiation therapy was delivered to 38.5% of prepectoral patients and to 22% of partial subpectoral patients. Mean follow-up was 8.7 and 13 months for the prepectoral cohort and partial subpectoral cohorts.The percentage of patients having at least 1 adverse event was 20.5% in the prepectoral and 22% in the partial subpectoral cohorts. The incidence of surgical-site infection and seroma was 8.1% and 4.8%, respectively, for the prepectoral cohort and 4.8% and 2.4%, respectively, for the partial subpectoral cohorts. Device explantation was 6.5% for the prepectoral and 7.2% for the partial subpectoral patients. Explantation did not occur in patients who had radiation or who had a BMI > 30. Four patients (6 breasts—7.2%) required conversion from partial subpectoral to prepectoral because of animation deformity.Prepectoral reconstruction is a viable alternative to partial subpectoral reconstruction. Proper patient selection is an important variable. Prepectoral reconstruction can be safely performed in patients with a BMI < 40 and in patients having postmastectomy radiation therapy.