BACKGROUNDS: Neoadjuvant therapy (NAT) is a cornerstone in the management of breast cancer (BC), enabling tumor downstaging and improved surgical options. METHODS: This study retrospectively analyzed 607 BC patients treated with NAT and surgery at IRCCS Humanitas Research Hospital, Milan, Italy, to compare long-term oncologic outcomes of breast-conserving surgery (BCS) versus mastectomy. Patient demographics, tumor characteristics, and treatment details were analyzed using descriptive statistics, logistic regression, and Cox proportional hazards models. RESULTS: Of the 607 patients, 54.7% underwent BCS, and 45.3% had mastectomy. BCS was associated with significantly superior 10-year outcomes compared to mastectomy, including disease-free survival (DFS, 75.2% vs. 71.1%, CONCLUSIONS: Our findings demonstrate the oncologic safety and potential superiority of BCS over mastectomy in NAT-treated BC patients, highlighting the importance of individualized surgical decision-making to optimize survival outcomes.