Background: The survival benefit of FOLFOXIRI plus bevacizumab (Triplet) over Doublet in patients (pts) with BRAF^V600E-mutant metastatic colorectal cancer (mCRC) remains controversial. We compared Triplet therapy with Doublet and explored the pts subgroups that could benefit from intensive chemotherapy (chemo) using real-world data. Methods: WJOG13219G was a multicenter, retrospective registry-based study of pts with BRAF^V600E-mutant mCRC who received first-line doublet or triplet chemo with/out molecular targeted agents in January 2014–December 2019. Primary analysis focused on pts who received VEGF inhibitor-containing chemo. To adjust pts background, the inverse probability of treatment weighting (IPTW) method based on propensity scores calculated by age, ECOG PS, and disease status (recurrent/metastatic) was used. Results: A total of 232 pts from 33 hospitals were registered. After excluding 18 pts treated with anti-EGFR antibody-containing regimen and 44 without any targeted agents, 79 pts with Triplet and 91 with Doublet were analyzed. Baseline pts disposition was as follows: median age, 61 y; male proportion, 51%; PS 0/1/≥2, 63%/32%/5%; recurrent/metastatic, 26%/74%; and right/left primary, 68%/32%. Significant differences were noted in age and PS between the two groups. At median follow-up of 24.0 months, no statistical difference was noted in progression-free survival (PFS) (median 9.7 months of Triplet vs. 7.8 months of Doublet, HR = 0.89, P = 0.49) and overall survival (OS) (median 18.7 vs. 18.3 months, HR = 0.87, P = 0.52). The objective response rate was 53% in the Triplet group and 41% in Doublet (P = 0.10). Curative surgery after chemo was more frequent in the Triplet group than in Doublet (13% vs. 3%, P = 0.02). Two pts (3%) in the Triplet group and 6 (7%) in Doublet received immunotherapy as subsequent chemo; 13 (16%) and 6 (7%) also received BRAF inhibitor-containing therapy. IPTW analysis showed no difference between the two groups in PFS (HR = 0.82, P = 0.07) and OS (HR = 0.92, P = 0.57). In the subgroup analysis, pts with right-sided primary tumor in the Triplet group showed favorable trends of PFS (HR, 0.87; 95% CI, 0.65–1.16) and OS (HR, 0.71; 95%CI, 0.50–1.01), whereas pts with left-sided tumor in the Triplet group showed the reverse trends of PFS (HR, 1.17; 95% CI, 0.77–1.78) and OS (HR, 1.68; 95% CI, 0.97–2.91). Conclusions: Some baseline characteristics were significantly different between real-world pts in the Triplet and Doublet groups. Although the Triplet group did not show any survival benefit compared with Doublet in the original and IPTW cohorts, pts with right-sided BRAF^V600E-mutant mCRC could benefit from Triplet therapy.