Background: Use of latissimus flap in prosthetic breast reconstruction after mastectomy is an established approach, particularly in patients who have failed breast-conserving therapy. This study presents a comparison of the prepectoral and the subpectoral approach for two-stage prosthetic breast reconstruction with a latissimus flap. Methods: A retrospective review of outcomes and complications was completed between the prepectoral group (n = 33 patients, 50 reconstructed breasts) and the subpectoral group (n = 22 patients, 36 reconstructed breasts). Results: The demographics were similar between the prepectoral and subpectoral groups in terms of mean age (52.4 vs. 52.5 years, p = 0.97), smoking history (15.1% vs. 13.6%; p = 1.00), radiation history (75.8% vs. 91.0%; p = 0.28), and mean length of follow-up (479 vs. 680 days; p = 0.07). The body mass index was significantly higher in the prepectoral group (27.6 vs. 25.2 kg/m(2); p = 0.03). Complications were similar between the groups in terms of hematoma (9.1% vs. 0.0%, p = 0.26), infection resulting in implant failure (9.1% vs. 4.5%, p = 0.64), thromboembolic events (3.0% vs. 4.5%, p = 1.0), donor site seroma (66.7% vs. 40.9%, p = 0.09), breast seroma (18.2% vs. 27.3%, p = 0.51), capsular contracture (9.1% vs. 4.5%, p = 0.64), animation deformity (39.4% vs. 50.0%, p = 0.58), and reoperation (24.2% vs. 22.8%, p = 1.00). Patient satisfaction scores were also similar between the groups (4.33 +/- 1.08 vs. 4.14 +/- 1.13, p = 0.52). Conclusions: The prepectoral approach for two-stage immediate prosthetic reconstruction with a latissimus flap has similar outcomes and complications to those of the subpectoral approach, yet obviating the need for any pectoralis major muscle dissection. (C) 2019 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.