Breast reconstruction following nipple-sparing mastectomy (NSM) in patients with large or ptotic breasts remains challenging because of the risk of ischemic complications and the difficulty in managing the redundant skin envelope. Staged mastopexy or breast reduction before the mastectomy/reconstruction has been shown to decrease the risk of complications and improve clinical outcomes. A retrospective analysis was conducted of patients with a genetic predisposition to breast cancer who underwent staged breast reduction/mastopexy before NSM and reconstruction in the authors' institution. In patients with in situ disease or invasive cancer, the first stage consisted of lumpectomy and oncoplastic reduction/mastopexy. Breast reconstruction at the second stage was performed with free abdominal flaps or breast implants and acellular dermal matrix. Data regarding the ischemic complications were recorded. In total, 47 patients (84 breasts) underwent this staged approach. All patients had a genetic predisposition to breast cancer. The time interval between the two stages was 11.5 months (range, 1.3 to 23.6 months). Twelve breasts (14.3%) were reconstructed with free abdominal flaps, six (7.1%) with tissue expanders, and 66 (78.6%) with permanent subpectoral implants and acellular dermal matrix. There was one case of postoperative superficial nipple-areola complex epidermolysis (1.2%), and two cases of partial mastectomy skin flap necrosis (2.4%). The mean follow-up time after completion of reconstruction was 8.3 months. Mastopexy or breast reduction before NSM and reconstruction is a safe procedure with a low risk of ischemic complications. Therapeutic, IV.