BACKGROUND:New surgical innovations of nipple-sparing mastectomy (NSM), such as endoscopic NSM (E-NSM) or robotic NSM (R-NSM), were emerging. However, there was a lack of evidence comparing the effectiveness and safety in the management of breast cancer. METHODS:A case-control comparison study was conducted for patients with breast cancer underwent E-NSM or R-NSM with immediate prosthesis breast reconstruction (IPBR) from July 2010 to February 2019 at a single institution to compare the clinical outcomes, learning curve, patient-reported cosmetic results, and medical cost. RESULTS:A total of 91 E-NSM and 40 R-NSM procedures were retrieved and analyzed. The surgical margin involvement rate in both R-NSM (2.5%) and E-NSM (4.4%) procedures were relatively low (P = 0.52). The R-NSM group was associated with higher satisfaction rates in terms of scar appearance, scar length, and surgical wound position compared with the E-NSM group. Compared with E-NSM, the R-NSM operation time took longer (241 ± 61 vs. 215 ± 70 min, P = 0.01), less blood loss (32 ± 29 vs. 79 ± 62 ml, P < 0.01), and higher medical cost (10,587 ± 554 vs. 6855 ± 936 U.S. dollars, P < 0.01). There was no statistically significant difference in nipple ischemia/necrosis or overall complication between R-NSM and E-NSM. In the learning curve analysis, it took the 27th procedure in E-NSM and 10th procedure in R-NSM to decrease operation time significantly. CONCLUSIONS:R-NSM was associated with higher wound-related satisfaction, lesser blood loss, and shorter learning curve compared with E-NSM, however, at the price of longer operation time and higher medical cost.