Background: The need for safe and effective therapies for untreated, BRAF V600E-mutated, unresectable locally advanced or metastatic colorectal cancer remains unmet. The purpose of this study was to compare the efficacy and safety of the VIC (Vemurafenib/Irinotecan/Cetuximab) regimen versus bevacizumab plus chemotherapy as first-line setting in Asian patients. Methods: In the single-center prospective cohort study, 78 untreated, BRAF V600E-mutant, locally advanced or metastatic CRC patients were enrolled. Every two weeks, the VIC regimen and bevacizumab plus doublet or triplet chemotherapy are administered. We evaluated the objective response rate (ORR), the disease control rate (DCR), and the conversion resection rate. In progression-free survival (PFS) and overall survival, the Kaplan-Meier method was utilized (OS). Results: In the evaluable population, 32 patients received VIC regimen and 35 patients received bevacizumab plus chemotherapy. The ORR and DCR in the VIC group were significantly higher than in the bevacizumab-therapy group (ORR: 68.8% versus 40.0%, P = 0.018; DCR: 100.0% versus 80.0%, P = 0.023). The VIC regimen was significantly superior to bevacizumab plus chemotherapy for PFS (median, 11.9 vs 7.9 months; hazard ratio [HR] = 0.48, 95% CI, 0.27-0.87; P = 0.012) and OS (median, 24.5 vs 14.4 months; HR = 0.36, 95% CI, 0.16-0.78; P = 0.007). In the VIC group, the conversion resection rate for liver metastases was 42.1% (8 of 19 patients), and for local CRC it was 66.7% (6 of 9 patients with initially unresectable local CRC). Rates of treatment-related adverse events of Grade 3 to 4 were 32.4% and 31.1% for the VIC regimen and bevacizumab plus chemotherapy, respectively. Conclusions: Among Asian patients with BRAF V600E-mutated advanced CRC, the VIC regimen was superior to bevacizumab plus chemotherapy in terms of tumor response and oncological survival, with a tolerable and manageable toxicity profile in the first-line setting. Clinical trial information: NCT05540951.