Several studies have been conducted on the effects and toxicity of adding oxaliplatin to fluorouracil-based or capecitabine-based chemoradiotherapy (CRT) regimens as significantly increasing the toxic response without benefit to survival. In this study, we further explored the role of these two postoperative CRT regimens in patients with pathological stage N2 rectal cancer.This study was a subgroup analysis of a randomized clinical trial. A total of 180 patients with pathological stage N2 rectal cancer were eligible, 85 received capecitabine with radiotherapy (RT), and 95 received capecitabine and oxaliplatin with RT. Patients in both groups received adjuvant chemotherapy [capecitabine and oxaliplatin (XELOX); or fluorouracil, leucovorin, and oxaliplatin (FOLFOX)] after CRT.At a median follow-up of 59.2 [interquartile range (IQR), 34.0-96.8] months, the three-year disease- free survival (DFS) was 53.3% and 64.9% in the control group and the experimental group, respectively [hazard ratio (HR), 0.63; 95% confidence interval (95% CI), 0.41-0.98; P=0.04]. There was no significant difference between the groups in overall survival (OS) (HR, 0.62; 95% CI, 0.37-1.05; P=0.07), the incidence of locoregional recurrence (HR, 0.62; 95% CI, 0.24-1.64; P=0.33), the incidence of distant metastasis (HR, 0.67; 95% CI, 0.42-1.06; P=0.09) and grade 3-4 acute toxicities (P=0.78). For patients with survival longer than 3 years, the conditional overall survival (COS) was significantly better in the experimental group (HR, 0.39; 95% CI, 0.16-0.96; P=0.03).Our results indicated that adding oxaliplatin to capecitabine-based postoperative CRT is safe and effective in patients with pathological stage N2 rectal cancer.Copyright ©2024 Chinese Journal of Cancer Research. All rights reserved.