Background: Beta defensin 1 (DEFB1) and 2 (DEFB4A) are antimicrobial peptides secreted from colonic epithelial cells in response to inflammation. DEFB1 has been shown to serve as a tumor suppressor, whereas high concentrations of DEFB4A are linked with angiogenesis. This study examines the impact of single nucleotide polymorphisms (SNPs) in beta-defensin pathways in two independent phase III trials: FIRE-3 and TRIBE. Methods: The OncoArray database containing 530K SNP markers provided by Illumina was used to find associations between clinical outcomes and 10 functional SNPs from DEFB1, DEFB4A, PPARG, NFKB1, MUC2, and TLR4 genes. Patients treated with first-line FOLFIRI/bevacizumab (bev) in the randomized phase III FIRE-3 trial (n = 107) and TRIBE trial (n = 215) served as discovery and validation cohorts respectively. The FIRE-3 FOLFIRI and cetuximab (cet) arm served as a negative control (n = 129). Results: A total of 451 patients were included. The NFKB1 rs3821958 SNP showed significant association with OS and PFS in overall pts and those with left-sided CRC. Compared to pts carrying the mutant A allele, those with the wild-type G/G genotype had a shorter median OS (19 vs 40 mts) and PFS (9.2 vs 11.7 mts) in both univariate ((OS: HR = 2.32, 95%CI 1.21-4.42, p = 0.006) (PFS: HR = 1.93, 95%CI: 1.11-3.37, p = 0.014)) and multivariable analysis ((OS: HR = 2.90, 95%CI 1.47-5.70, p = 0.002) (PFS: HR = 2.08, 95%CI:1.18-3.67, p = 0.012)). This finding was validated in TRIBE, where carriers of G allele had shorter PFS in univariate analysis (HR = 1.44, p = 0.019). Opposite results were observed in pts receiving cet, where G/G carriers had improved OS in univariate analysis (HR = 0.46, p = 0.048). Pts with left-sided CRC who carried the wild-type allele had poorer OS and PFS in both trials. Conclusions: NFKB1 rs3821958 SNP is known to activate DEFB1 and is downstream of EGFR. Harboring a mutant allele in this SNP confers a mortality benefit in left-sided and overall pts treated with bev, and worsens OS in pts receiving cet. Hence, NFKB1 could serve as an important predictive biomarker. Future studies are warranted to further elucidate its role in colorectal cancer.