ABSTRACT: Background and Objectives: Whether post-mastectomy radiotherapy (PMRT) could improve prognosis for T1-2 breast cancer patients with one to three lymph node metastases remains controversial. The present study aimed to determine the significance of PMRT in patients with T1-2N1M0 breast cancer. Methods: Data of 45,646 patients from the Surveillance, Epidemiology, and End Results (SEER) database were analyzed; 12,585 matched patients were divided into a PMRT group and non-radiotherapy group (no-PMRT), respectively, using the propensity score matching method. Univariate and multivariate analyses were performed to determine the prognostic factors of breast cancer, and subgroup analysis was performed according to the number of lymph node metastases. Results: With the median follow-up of 62 months, 5-year cancer-specific survival was 91.48% in the PMRT group and 91.88% in the no-PMRT group (P = 0.405). PMRT did not improve the breast cancer-specific survival (BCSS) in patients with stage T1-2N1M0 (HR = 0.99, 95% CI = 0.92-1.06, P = 0.715). In subgroup analysis, radiotherapy improved the BCSS in patients with three nodes positive, with the 5-year BCSS at 88.5% in the radiation group and 86.6% in the no-radiation group (HR = 0.78, 95% CI = 0.65-0.90, P < 0.001). In patients with two nodes positive, 5-year BCSS was 90.3% in the PMRT group and 89.5% in the no-PMRT group, with no significant difference between the two groups (HR = 0.96, 95% CI = 0.85-1.09, P = 0.552). In patients with one node positive, 5-year BCSS was higher in the no-PMRT group (92.1%) than that in the PMRT group (90.8%); radiotherapy increased the cancer-related death compared with those who did not receive it (HR = 1.21, 95% CI = 1.08-1.36, P = 0.002). Conclusion: The benefit of PMRT in T1-2N1M0 patients was obviously different, and the recommendation of PMRT for this population should be individualized. PMRT should be considered for patients with three nodes positive, should be suggested cautiously in those with two nodes positive, and could be omitted in those with one node positive.