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Initially performed only in prophylactic cases, indications for nipple-sparing mastectomy have expanded. Trends and surgical outcomes stratified by nipple-sparing mastectomy indication have not yet been fully examined.Demographics and outcomes for all nipple-sparing mastectomies performed from 2006 to 2017 were compared by mastectomy indication.A total of 1212 nipple-sparing mastectomies were performed: 496 (40.9 percent) for therapeutic and 716 (59.1 percent) for prophylactic indications. Follow-up time was similar between both the therapeutic and prophylactic nipple-sparing mastectomy groups (47.35 versus 46.83 months, respectively; p = 0.7942). Therapeutic nipple-sparing mastectomies experienced significantly greater rates of major (p = 0.0165) and minor (p = 0.0421) infection, implant loss (p = 0.0098), reconstructive failure (p = 0.0058), and seroma (p = 0.0043). Rates of major (p = 0.4461) and minor (p = 0.2673) mastectomy flap necrosis and complete (p = 0.3445) and partial (p = 0.7120) nipple necrosis were equivalent. The overall rate of locoregional recurrence/occurrence per nipple-sparing mastectomy was 0.9 percent: 2.0 percent in therapeutic nipple-sparing mastectomies and 0.1 percent in prophylactic nipple-sparing mastectomies (p < 0.0001).Approximately 40 percent of nipple-sparing mastectomies are currently performed for therapeutic indications. Therapeutic nipple-sparing mastectomies had higher rates of infectious complications and reconstructive failure. Rates of locoregional cancer recurrence/occurrence are low, but occur significantly more often after therapeutic nipple-sparing mastectomy.Therapeutic, III.