Background: Vitamin D mainly exerts its inhibitory influence on the development of colon cancer by inhibiting the canonical Wnt signaling pathway, whereas its role in modulating the non-canonical Wnt pathway is less clear. Additionally, there are preliminary data suggesting that vitamin D may inhibit tumor angiogenesis. We hypothesize that SNPs in genes involved in Vitamin D and non-canonical Wnt5a signaling are associated with outcome in metastatic colorectal cancer (mCRC) patients (pts) treated with first-line FOLFIRI and bevacizumab (bev). Methods: 295 pts with mCRC enrolled in the phase III FIRE-3 trial and treated with first-line FOLFIRI and bev were included in this study. Genomic DNA was extracted from formalin fixed paraffin embedded tissue. 10 functional SNPs in 10 genes (GC, CAMK2B, CYP24A1, CYP27B1, VDR, DKK1, CST5, ROR2, Wnt5a, CASR) were analyzed by PCR-based direct sequencing. Results: Baseline characteristics were as follows: female/male = 99/196; median age = 65y; primary tumor site right/left = 74/215;median PFS/OS = 10.2/24.2 months. G alleles carriers of the GC rs4588 SNP encoding for the vitamin D binding protein showed a longer median overall survival (OS) than those with a TT genotype (25.0 vs 15.9 months) in both univariate (HR 2.18, p = 0.002) and multivariate analysis (HR 1.73, p = 0.043). Pts with a CC genotype of the Wnt5a rs1829556 SNP yielded a higher response rate compared to those harboring any T allele (75% vs 56%, p = 0.006) which also translated into better progression-free (PFS) (11.5 vs 10.1 months, HR 1.45, p = 0.016) and OS (29.0 vs 22.1 months, HR 1.56, p = 0.011). These associations remained significant in multivariate analysis. Conclusions: This is the first report demonstrating that the GC rs4588 SNP encoding for the vitamin D binding protein might serve as a prognostic marker in pts with mCRC. Additionally we provide the first evidence that the Wnt5a rs1829556 SNP might be both a prognostic and predictive biomarker for mCRC pts treated with first-line FOLFIRI and bev. Targeting the Wnt5a ligand and the vitamin D binding protein might be a promising approach to improve our treatment options against mCRC.