Background: Evidence regarding the earliest timing of initiating adjuvant chemotherapy for safely maximizing its efficacy is lacking. The postoperative recovery interval has been reduced because of the minimally invasive surgery and enhanced recovery after surgery protocols. This trial evaluated the the safety and oncological efficacy of early adjuvant chemotherapy compared with conventional adjuvant chemotherapy. Report on the short-term outcomes of toxicity, postoperative complications, and quality of life of this trial has been published previously. Herein, we present the primary endpoint. Methods: A multicenter, randomized (1:1), open-label, phase III trial was conducted to compare early adjuvant chemotherapy with conventional adjuvant chemotherapy in patients with stage III colon cancer. Patients who underwent radical surgery and had stage III colon cancer confirmed by histopathological assessment were screened and randomized into the early adjuvant chemotherapy group (EAC group) or the conventional adjuvant chemotherapy group (CAC group). Adjuvant chemotherapy with FOLFOX was administered between postoperative days 10 and 14 in the EAC group, and between postoperative days 24 and 28 in the CAC group. The primary endpoint was 3-year disease-free survival, defined as the time from the date of surgery to the earliest date of recurrence, assessed in the intention-to-treat population. The secondary endpoints were toxicity, postoperative complications, quality of life, and overall survival. (ClinicalTrials.gov, NCT01460589) Results: Between 9 September 2011 and 6 March 2020, 443 patients consented to randomization at eight sites. The intention-to-treat population included 423 patients (217 in the EAC group and 221 in the CAC group), and the per-protocol population included 380 patients (192 in the EAC group and 188 in the CAC group). There was no statistically significant difference in overall toxicity (28.1% in the EAC group and 28.2% in the CAC group, p=0.244) between the two groups. At a median follow-up of 59.4 months (IQR 59.8-63.6), 3-year disease-free survival rates were 86.9% (95% CI 82.5-91.5) in the EAC group versus 86.6% (82.2-91.3) in the CAC group (hazard ratio 0·67, 95% CI 0·69–1.78; p=0·672). Three-year overall survival rates were 93.0% (95% CI 89.6-96.5) in the EAC group versus 94.5% (91.5-97.6) in the CAC group (hazard ratio 0.31, 95% CI 0.76-2.35; p=0.313). In the per-protocol analysis, both 3-year disease-free survival and overall survival were comparable between the two groups. Conclusions: To the best of our knowledge, this is the first randomized controlled trial investigating the time required for adjuvant chemotherapy for colon cancer. The findings reveled that adjuvant chemotherapy within 2 weeks after surgery for stage III colon cancer did not prolong disease-free survival. Clinical trial information: NCT01460589.