Purpose: To compare the efficacy and safety of high-dose vitamin C plus FOLFOX f bevacizumab versus FOLFOX f bevacizumab as first-line treatment in patients with metastatic colorectal cancer (mCRC).Patients and Methods: Between 2017 and 2019, histologically confirmed patients with mCRC (n = 442) with normal glucose-6-phosphate dehydrogenase status and no prior treatment for met-astatic disease were randomized (1:1) into a control (FOLFOX f bevacizumab) and an experimental [high-dose vitamin C (1.5 g/kg/ d, intravenously for 3 hours from D1 to D3) plus FOLFOX f bevacizumab] group. Randomization was based on the primary tumor location and bevacizumab prescription.Results: The progression-free survival (PFS) of the experimental group was not superior to the control group [median PFS, 8.6 vs. 8.3 months; HR, 0.86; 95% confidence interval (CI), 0.70-1.05; P = 0.1]. The objective response rate (ORR) and overall survival (OS) of the experimental and control groups were similar (ORR, 44.3% vs. 42.1%; P = 0.9; median OS, 20.7 vs. 19.7 months; P = 0.7). Grade 3 or higher treatment-related adverse events occurred in 33.5% and 30.3% of patients in the experimental and control groups, respec-tively. In prespecified subgroup analyses, patients with RAS muta-tion had significantly longer PFS (median PFS, 9.2 vs. 7.8 months; HR, 0.67; 95% CI, 0.50-0.91; P = 0.01) with vitamin C added to chemotherapy than with chemotherapy only.Conclusions: High-dose vitamin C plus chemotherapy failed to show superior PFS compared with chemotherapy in patients with mCRC as first-line treatment but may be beneficial in patients with mCRC harboring RAS mutation.