PURPOSE: The aim of this study was to investigate the survival benefits of postoperative radiotherapy (PORT) in patients with resectable esophageal cancer (EC) after neoadjuvant therapy in the Immunotherapy era. METHODS: The study was designed as a retrospective cohort study, which included a total of 733 patients with EC from the SEER database and a single-center cohort. We used propensity score matching (PSM) to equilibrate patient characteristics. The investigation incorporated Kaplan-Meier survival analysis and the Cox proportional risk regression model to assess outcomes. RESULTS: PORT did not significantly improve survival in the overall cohort, with a median overall survival of 38 months (p=0.56) in the SEER cohort and 39 months (p=0.75) in the Chinese cohort. However, in the immunotherapy subgroup, the Chinese cohort demonstrated that immunotherapy combined with PORT significantly improved survival (p=0.044).Multivariate Cox regression analysis demonstrated that patients aged 50-59 years (HR=5.93, 95% CI: 1.67-21.06) and those aged ≥70 years (HR=10.96, 95% CI:3.04-39.56) had increased survival risks compared to patients aged <
50 years. Additionally, ypT3-4 stage patients exhibited a higher risk than those with ypT1-2 stage (HR=2.12, 95% CI: 1.14-3.93, p=0.017).Similar trends were observed in cT3-4 staging, R1/R2 and no immunotherapy. Lymph node metastasis also showed a progressive relationship with survival risk, with patients categorized as ypN1 (HR=1.90), ypN2 (HR=4.24), and ypN3 (HR=6.68) experiencing increasingly higher risks (p<
0.05). CONCLUSIONS: The collaborative effect of immunotherapy and PORT potentially enhances survival outcomes for patients with EC. However, further prospective research is essential to confirm our results.