Background and Aims In recent years, the implementation of endoscopic nipple-sparing mastectomy (NSM) with prosthetic breast reconstruction has increased. Various approaches for endoscopic surgery exist, with the axillary and lateral approaches being the most common. However, comparative studies on the surgical outcomes of these two approaches are limited. Therefore, this study was performed to compare the efficacy of endoscopic NSM with prosthetic reconstruction via the axillary and lateral approaches, providing clinical references for selecting the appropriate endoscopic surgical approach.Methods The clinical data of 152 breast cancer patients who underwent endoscopic NSM with prosthetic breast reconstruction from January 2016 to October 2022 in the Department of Breast and Thyroid Surgery of the First Affiliated Hospital of the Army Medical University were retrospectively collected. The patients were divided into the axillary approach group (78 cases) and the lateral approach group (74 cases) based on the surgical approach. Relevant clinical variables were compared between the two groups.Results There was no statistically significant difference in baseline data between the two groups (all P>0.05). The lateral approach group had a shorter operative time (211.50 min vs. 250.00 min, P<0.001) and less drainage volume (300.50 mL vs. 504.50 mL, P<0.001) compared to the axillary approach group. The axillary approach group had a significantly higher proportion of prepectoral prosthetic breast reconstruction compared to the lateral approach group (24.4% vs. 6.8%, P=0.003). There were no statistically significant differences between the two groups in intraoperative blood loss, postoperative drainage time, postoperative hematoma, infection, seroma, nipple-areola or skin flap necrosis, or capsular contracture rates (all P>0.05). Six-month postoperative follow-up showed no significant differences between the two groups in breast shape, quality of life, and postoperative satisfaction (axillary approach: 91.0% vs. lateral approach: 91.9%) (all P>0.05). Additionally, there were no significant differences in distant metastasis, local recurrence, or overall survival rates between the two groups (all P>0.05).Conclusion Both the axillary and lateral approaches for NSM with prosthetic breast reconstruction are safe and effective, with no differences in aesthetic outcomes. The axillary approach is suitable for prepectoral prosthetic implantation, while the lateral approach is simpler, shortens operation time, preserves the pectoral fascia, and allows for subpectoral prosthetic implantation without the need for a reinforcement mesh.