The purpose of this study is to assess the value of internal mammary node irradiation (IMNI) in patients receiving postoperative radiotherapy after neoadjuvant chemotherapy (NAC) using modern systemic therapy. Between 2001 and 2009, 521 consecutive patients with clinical stage II-III breast cancer received NAC and postoperative radiotherapy. With a consistent policy, the treating radiation oncologist either included (N = 284) or excluded (N = 237) the internal mammary node in the treatment volume. Anthracycline- and taxane-based chemotherapy was provided to 482 (92.5 %) patients. To account for the unbalanced characteristics between the two groups, we performed propensity score matching and covariate adjustment using the propensity score. The median follow-up duration was 71 months (range 31-153 months). The 5-year disease-free survival (DFS) with and without IMNI was 81.8 and 72.7 %, respectively (p = 0.019). The benefit of IMNI varied according to patient characteristics such that it was more apparent in patients with N1-2 disease, inner/central location, and triple-negative subtype. After adjusting for all potential confounding variables, IMNI was independently associated with improved DFS (p = 0.049). The significant effect of IMNI on DFS was sustained after propensity score matching (p = 0.040) and covariate adjustment using the propensity score (p = 0.048). Symptomatic radiation pneumonitis developed in 9 (3.2 %) patients receiving IMNI. Our results indicated that IMNI was associated with a significant improvement in DFS with low toxicity rate for breast cancer patients receiving NAC. Further prospective studies are warranted to confirm the effect of IMNI in the NAC setting.