PURPOSE: This study aims to determine the optimal time to perform sentinel lymph node biopsy (SLNB) for patients with clinically node-negative (cN) disease following neoadjuvant chemotherapy (NAC). METHOD: From April 2008 to April 2018, 592 patients with breast cancer underwent after NAC were included in this study. Patients with cN before and ycN disease after NAC received SLNB and axillary lymph node dissection (ALND) in case of positive sentinel lymph nodes (SLNs). For patients with clinically node-positive (cN) disease, the axillary surgery is based on the doctor's decision. RESULT: In general, 17.6% (104/592) of patients achieved total pathologic complete response (pCR), which was 6.9%, 33.3%, 32.3% and 15.3%, respectively, among patients with hormone receptor (HR) positive/ human epidermal growth factor receptor-2 (HER-2) negative (HR+/HER2-) subtype, triple-negative (TN) subtype, HER-2 positive (HER2+) subtype with and without targeted therapy (p < 0.001). Among the 525 cN patients, the axillary nodal pCR (apCR) rate was 34.5%, and the apCR rate was significantly higher in patients with HER2+ (58.6% with and 28.2% without targeted therapy respectively) and TN subtype (53.2%) than that in patients with HR+/HER2-subtype (21.2%, p < 0.001). Among the 67 cN patients, the positive rate of SLNs was 19.4% (13/67), which was 28.1% (9/32), 13.3% (2/15) and 10.0% (2/20), respectively, among patients with HR+/HER2-, TN and HER2 + subtypes. CONCLUSION: The pCR rates were significantly related to molecular subtype. Combining the apCR rates in different molecular subtypes of cN patients and the excellent locoregional control of AOSOG Z0011 and AMAROS trials in cN patients, it would be preferable to perform SLNB prior to NAC for cN patients with HR+/HER2- subtype, and SLNB after NAC for those cN patients with TN and HER2+ subtype to increase the chance of avoiding ALND. Among cN patients, TN and HER2 + subtypes would benefit more from axillary de-escalating surgery after NAC than HR+/HER2- subtype.