Background: Adjuvant chemotherapy is the recommended standard treatment for resected stage III and high-risk stage II colon cancer, but disease recurrence remain common. Perioperative chemotherapy has proved effective in several tumors, but not in colon cancer. We aimed to assess whether perioperative chemotherapy could improve outcomes in patients with locally advanced colon cancer. Methods: In this multicenter, randomized, phase 3 trial, participants were recruited from 28 hospitals in China. Eligible patients were aged 18-75 years, had a colon adenocarcinoma, with radiologically staged locally advanced (T3 with ≥5 mm invasion beyond the muscularis propria or T4 assessed by CT). Patients were randomly assigned (1:1) to either the experimental group or standard of care group, stratified by center, cT stage, and cN stage. The experimental group received 3 months of neoadjuvant chemotherapy with mFOLFOX6 or CAPOX, then surgery, then 3 months of adjuvant chemotherapy. The standard of care group received immediate surgery, and optional adjuvant chemotherapy (per physician’s discretion according to pathological stage ). The primary endpoint was disease-free survival assessed in the intention-to-treat population at 3 years. Results: Between January 6, 2016, and April 3, 2021, 752 patients were enrolled and randomly assigned to a treatment, of whom 744 were eligible (371 in the experimental group; 373 in the standard of care group). At a median follow-up of 32.5 months (IQR 19.2-45.7), 3-year disease-free survival rates were 78.7% (95%CI 73.8-83.5) in the experimental group and 76.6% (95%CI 71.8-81.4) in the standard of care group (stratified HR 0.83, 95%CI 0.60-1.15; p = 0.138). A pathological complete response was achieved in 26 (7%) of 371 patients in the experimental group. 69 (19%) patients in the experimental group had low pathological disease stage (pT0-2N0) compared with 16 (4%) of 373 in the standard of care group (p < 0.0001). 3-year overall survival rates were 94.9% (95%CI 92.1-97.7) in the experimental group and 88.6% (95%CI 84.6-92.5) in the standard of care group (stratified HR 0.47, 95%CI 0.25-0.87; p = 0.012). The post hoc subgroup analyses revealed perioperative chemotherapy induced an increase in disease-free survival in female patients (HR 0.54, 95%CI 0.31-0.83; p = 0.025). Conclusions: In patients with locally advanced colon cancer, perioperative chemotherapy with mFOLFOX6/CAPOX increased chance of pathological downstaging, but did not improve disease-free survival compared with standard of care. Clinical trial information: NCT02572141.