This study’s primary objective was to evaluate the efficacy and safety of high-dose vitamin C in combination with FOLFOX ± bevacizumab against FOLFOX ± bevacizumab as first-line treatment for patients with metastatic colorectal cancer (mCRC). Histologically confirmed patients with mCRC (n = 442) with normal glucose-6-phosphate dehydrogenase status and no prior treatment for metastatic disease were randomized (1:1) between 2017 and 2019 into a control (FOLFOX ± bevacizumab) and an experimental (high-dose vitamin C (1.5 g/kg/d, intravenously for 3 hours from D1 to D3) plus FOLFOX ±  bevacizumab) group. Primary tumor site and bevacizumab treatment were used as randomization criteria. Neither the experimental nor the control groups had better progression-free survival (PFS) [median PFS, 8.6 vs. 8.3 months; HR, 0.86; 95% CI, 0.70-1.05; P=0.1]. The median overall survival (OS) for those in the treatment and control groups was also quite close at 20.7 months (objective response rate ORR, 44.3% vs. 42.1%; P=0.9) and 19.7 months (P=0.7). Around 35% of patients in the study’s experimental group and 30.3% of those in the control group experienced treatment-related side events of grade 3 or higher. Patients with RAS mutations who received vitamin C in addition to chemotherapy had a significantly higher progression-free survival (PFS; median PFS, 9.2 vs. 7.8 months; HR, 0.67; 95% CI, 0.50-0.91; P=0.01) than those who received chemotherapy alone. Patients with metastatic colorectal cancer (mCRC) treated first with high-dose vitamin C with chemotherapy did not have better progression-free survival (PFS) than patients treated initially with chemotherapy alone but may benefit from this approach if their mCRC contains the RAS mutation.