OBJECTIVE: The goal of this study was to investigate whether neoadjuvant chemoradiotherapy (NCRT) plus total mesorectal excision (TME) would improve the outcome of patients with MRI-defined high-risk rectal cancer compared with TME plus adjuvant chemotherapy (ACT) or TME alone. METHODS: We retrospectively enrolled 362 patients with MRI-defined high-risk rectal cancer who were treated with NCRT plus TME, TME plus ACT, or TME alone between January 2008 and August 2018. Cases with a high-risk tumor stage, positive extramural venous invasion, or mesorectal fascia involvement on baseline MRI were considered cases of high-risk rectal cancer. We matched patients treated with NCRT plus TME to patients treated with TME plus ACT and to those treated with TME alone. Kaplan-Meier curves were used to compare local recurrence (LR), disease-free survival (DFS), and overall survival (OS) rates. RESULTS: The cumulative 3 year LR rate in the matched NCRT plus TME group was more favorable than in the TME plus ACT group (0% 5.1%; = 0.037; = 98) and in the TME alone group (0% 11.5%; = 0.016; = 61). Patients who received NCRT plus TME demonstrated better cumulative 3 year DFS rates than patients treated with TME plus ACT (85.7% 65.3%; = 0.009) or with TME alone (86.9% 68.9%; = 0.046). No difference in OS was observed among the groups. CONCLUSION: NCRT may improve DFS and LR rates in patients with MRI-defined high-risk rectal cancer when compared with TME plus ACT or TME alone. ADVANCES IN KNOWLEDGE: This study illustrated the specific benefit of NCRT on the outcome measures of MRI-defined high-risk rectal cancer compared with TME plus ACT or TME alone, which was not clearly clarified in previous studies enrolling all patients with Stage II/III rectal cancer.