Background: It’s presented the results of a phase III trial of short-term radiotherapy (SCRT) combined with chemotherapy versus long-term chemoradiotherapy (LCRT) in patients with locally advanced rectal cancer (LARC). Methods: Patients with distal or middle third, T3-T4 and/or N+ rectal adenocarcinomas diagnosed by MRI, were randomly assigned to experimental group or control group. In experimental group, patients received SCRT (25 Gy / 5 fractions / 5 days), followed by four courses of CAPOX. In control group, patients received LCRT (50 Gy / 25 fractions / 35 days with concurrent capecitabine). Surgery was recommended in both groups and performed 6-8 weeks after preoperative treatment. Two or six courses of CAPOX was prescribed as the postoperative chemotherapy in experimental group and control group, respectively. This trial was a multicenter, open-label, randomized, noninferior, phase III study, and all the patients were from 16 hospitals of China. The primary endpoint for this study was 3-year disease-free survival (DFS). Results: From Aug 30, 2015 to Aug 27, 2018, 599 patients were enrolled and entered random. Finally, 591 intention-to-treat (ITT) populations were included in the analysis, 298 patients assigned to SCRT followed by chemotherapy and 293 to CRT. For the experimental group and control group, cT3 and cT4 accounted for 82.3% vs. 84.6% and 15.4% vs. 12.3%, respectively, and approximately 85% were mrN positive (85.6% vs. 84.0%). As a whole, the completion and full-dose completion rates of preoperative treatment were 82.6% vs. 95.2% (p＜0.001) and 74.8% vs 93.2% (p＜0.001) in the experimental and control groups, respectively. Among the 465 patients who received surgery, 16.6% and 11.8% of them achieved pCR (p=0.134), respectively. Accounting for cCR after preoperative treatment, the total rate of pCR+cCR in experimental group was 22.5% and significantly higher than control group (12.6%, p=0.001). With median follow-up 35.0 months, the HR between experimental and control of DFS was 0.883, with 1-sided noninferiority p-value <0.001, so the noninferiority hypothesis was confirmed. The probability of DFS and OS at 3 years was 64.5% and 86.5% in the experimental group compared with 62.3% and 75.1% in control group. It’s observed the OS rate of the experimental group was significantly higher than that of the control group (p=0.036) and no significant difference in metastasis-free survival or loco-regional recurrence was observed. Conclusions: For LARC with high risk factors, SCRT combined with sequential chemotherapy was noninferior to CRT and could be used as an alternative to LCRT. Meanwhile, SCRT combined with chemotherapy presented a higher cCR+pCR and 3-year overall survival rates as compared with CRT. However, the long term results need to be further followed up. (ClinicalTrails No.: NCT02533271). Clinical trial information: NCT00833131