Purpose <p>This study aims to determine the potential association of postmastectomy radiotherapy and survival in patients with clinically node-positive axillary breast cancer who achieved ypN0 after neoadjuvant chemotherapy.</p> Methods <p>We conducted a retrospective cohort study using the National Cancer Database. Eligible patients were women aged 18–80 with cT1-2, cN+ invasive breast cancer and achieving ypN0 status. Inverse probability weighting (IPW)-based analyses were used to assess the differences in overall survival (OS) between the radiotherapy and no radiotherapy groups. Absolute 5-year OS rates between the two groups were analyzed by nonparametric sliding-window subpopulation treatment effect pattern plot (STEPP) analysis. Sensitivity analyses were conducted using multivariable Cox regressions.</p> Results <p>We identified 3,351 patients who met eligibility criteria, of whom 57.0% (<i>N</i> = 1,910) did not receive radiotherapy and 43.0% (<i>N</i> = 1,441) did receive radiotherapy. No significant differences in OS were observed between the radiotherapy and non-radiotherapy groups after adjustment (hazard ratio = 1.01, <i>P</i> = .96). The STEPP analysis demonstrated no significant differences between the RT and no RT groups, regardless of the composite risk. Subgroup analyses showed that the difference in OS rates between the two groups was significantly correlated with cN category, and the advantage associated with radiotherapy receipt was only observed in cN2-3 patients but not in cN1 patients (hazard ratio = 0.55; <i>P</i>-interaction = 0.024).</p> Conclusions <p>This study further supports the NSABP B51 findings, suggesting that omitting postmastectomy radiotherapy may be reasonable for cT1-2N1M0 patients who achieved ypN0. However, postmastectomy radiotherapy may be a consideration for patients with more advanced nodal disease (cN2-3) who achieve ypN0 status after NAC, indicating that a more tailored approach may be warranted.</p>