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Background: Nipple-sparing mastectomy (NSM) is increasingly used in women with breast cancer who are not eligible for conservative surgery, but extensive outcome data are lacking and indications have not been established. Objective: The aim of this study was to assess the oncological outcomes of NSM in a large series of patients with invasive or in situ breast cancer treated at a single center. Methods: We analyzed 1989 consecutive women who had an NSM in 2003–2011, for invasive (1711 patients) or in situ cancer (278 patients) at the European Institute of Oncology, Italy, and followed-up to December 2016. Endpoints were local recurrences, recurrences in the nipple-areola complex (NAC), NAC necrosis, and overall survival (OS). Results: After a median follow-up of 94 months (interquartile range 70–117), 91/1711 (5.3%) patients with invasive cancer had local recurrence (4.8% invasive disease, 0.5% in situ disease), and 11/278 (4.0%) patients with in situ disease had local recurrence (1.8% invasive disease, 2.2% in situ disease). Thirty-six (1.8%) patients had NAC recurrence, 9 with in situ disease (4 invasive and 5 in situ recurrences), and 27 with invasive disease (18 invasive and 9 in situ recurrences). NAC loss for necrosis occurred in 66 (3.3%) patients. There were 131 (6.6%) deaths, 109 (5.5%) as a result of breast cancer. OS at 5 years was 96.1% in women with invasive cancer and 99.2% in women with in situ disease. Conclusions: The findings in this large series, with a median follow-up of nearly 8 years, indicate that NSM is oncologically safe for selected patients. The rate of NAC loss was acceptably low.