Background: Residual axillary lymph node involvement after neoadjuvant systemic therapy (NST) is the determining factor for postmastectomy radiation therapy (PMRT). Preoperative identification of patients needing PMRT is essential to enable shared decision-making when choosing the optimal timing of breast reconstruction. We determined the risk of positive sentinel lymph node (SLN) after NST in clinically node-negative (cN0) breast cancer. Methods: All cT1-3N0 patients treated with NST followed by mastectomy and SLNB between 2010 and 2016 were identified from the Netherlands Cancer Registry. Rate of positive SLN for different breast cancer subtypes was determined. Logistic regression analysis was performed to determine correlated clinicopathological variables with positive SLN. Results: In total 788 patients were included, of whom 25.0% (197/788) had positive SLN. cT1-3N0 ER+HER2+, cT1-3N0 ER−HER2+ , and cT1-2N0 triple-negative patients had the lowest rate of positive SLN: 7.2–11.5%, 0–6.3%, and 2.9–6.2%, respectively. cT1-3N0 ER+HER2− and cT3N0 triple-negative patients had the highest rate of positive SLN: 23.8–41.7% and 30.4%, respectively. Multivariable regression analysis showed that cT2 (odds ratio [OR] 1.93; 95% confidence interval [CI] 1.01–3.96), cT3 (OR 2.56; 95% CI 1.30–5.38), grade 3 (OR 0.44; 95% CI 0.21–0.91), and ER+HER2− subtype (OR 3.94; 95% CI 1.77–8.74) were correlated with positive SLN. Conclusions: In cT1-3N0 ER+HER2+, cT1-3N0 ER−HER2+, and cT1-2N0 triple-negative patients treated with NST, immediate reconstruction can be considered an acceptable option due to low risk of positive SLN. In cT1-3N0 ER+HER2− and cT3N0 triple-negative patients treated with NST, risks and benefits of immediate reconstruction should be discussed with patients due to the relatively high risk of positive SLN.