Short-term radiotherapy with preoperative chemotherapy followed by surgery (total neoadjuvant therapy, TNT) was compared to standard long-term chemoradiotherapy in patients with locally advanced rectal cancer. At a median follow-up of 35.0 months, 3-year DFS was 64.5% and 62.3% in the TNT and CRT groups, respectively. There was no significant difference in metastasis-free survival or locoregional recurrence, but the TNT group had better 3-year overall survival than the CRT group (86.5% v 75.1%; P = .033). Treatment effects on DFS and overall survival were similar regardless of prognostic factors. The prevalence of acute grade III-V toxicities during preoperative treatment was 26.5% in the TNT group versus 12.6% in the CRT group (P < .001).