Background: B cells are recognized for their immune activation and lymph-angiogenesis, which attract us to clarify the correlation between B cells and the effect of bevacizumab in cancer patients. We thus investigated whether genetic polymorphisms in Tfh cell/ B cell pathway could predict clinical outcomes in metastatic colorectal cancer (mCRC) patients with bevacizumab-based chemotherapy in first-line treatment. Methods: Genomic DNA was extracted from 451 samples of three independent cohorts: a discovery cohort of 215 patients with bevacizumab plus FOLFIRI in TRIBE (NCT00719797); a validation cohort of 107 patients with bevacizumab plus FOLFIRI in FIRE-3 (NCT00433927); a control cohort of 129 patients with cetuximab plus FOLFIRI in FIRE-3. The OncoArray including 530K single nucleotide polymorphisms (SNPs) from Illumina was used in this study. The correlation between selected SNPs in Tfh cell/ B cell pathway (CCL19, CCL21, CCR7, CXCL13, CXCR5, and S1PR2) and clinical outcomes were analyzed. Results: In the discovery cohort, patients with any CXCL13 rs355687 C allele had shorter OS than those with T/T variant (22.9 vs. 30.8 months, HR 1.36, 95%CI: 1.00–2.86, P = 0.050), which remained significant in multivariable analysis (HR 1.51, P = 0.013); they also showed a trend of lower response rate (51 vs. 63%, P = 0.093); patients with any CCL21 rs11574915 C allele had shorter OS than those with A/A variant (25.6 vs. 27.9 months) in both univariate (HR 1.43, 95%CI: 1.01–2.02, P = 0.043) and multivariable analyses (HR 1.50, P = 0.030). In the validation cohort, patients with any CXCL13 rs355687 C allele had a trend which showed lower response rate than those with T/T variant (56 vs. 71%, P = 0.099). The findings were not detected in the control cohort. Conclusions: Genetic polymorphisms of CXCL13 and CCL21 may impact the angiogenic environment and patients survivals. They are impacting efficacy of bevacizumab-based chemotherapy in first-line treatment.