Background: The optimal time from surgery to the start of chemotherapy in colon cancer is unknown. We evaluated the impact on survival of intraportal chemotherapy (IPC) administrated during surgery plus adjuvant chemotherapy (AC) as treatment for stage II and III colon cancer. Methods: Patients with stage II or stage III colon cancer were randomly assigned to receive IPC plus mFOLFOX6 (OCTREE) or mFOLFOX6 alone. The primary end point was disease-free survival (DFS). Secondary endpoints included metastasis-free survival (MFS), overall survival (OS) and safety. Results: The intent-to-treat population comprised 237 patients. After a median follow-up of 44 months, The 3-year DFS rate was 85.2% (95% Cl 81.9 to 88.4) with OCTREE and 75.6% (95% Cl 71.7 to 79.4) with mFOLFOX6 alone (P = .030). The hazard ratio (OCTREE versus mFOLFOX6) was 0.66 (95% CI, 0.43 to 0.90, P = .016). The 3-year MFS rates were 87.6% versus 78.0%, when compared OCTREE with mFOLFOX6, the hazard ratio was 0.59 (95% CI, 0.38 to 0.92, P = .023). Patients in OCTREE arm had decreased distant metastases events (12.7% versus 22.7%; P= .044) compared with those in mFOLFOX6 arm. Grade 3 hepatic toxicity was observed in 1.7% of patients receiving OCTREE within two weeks after surgery, and could be cured with medicine. Only one patient died as a result of any cause within 6 months of receiving chemotherapy, with no significant difference between regimens. Conclusions: Intraoperative intraportal chemotherapy combined with mFOLFOX6, reduced the occurrence of distant metastasis, and therefore improved DFS in patients with stage II and stage III colon cancer. Clinical trial information: NCT01972503.