Background: Macrophages, particularly M2, enhance tumor progression by stimulation of angiogenesis, acceleration of tumor invasion, and suppression of immunosurveillance. CCL2 promotes the polarization into M2 whereas histidine-rich glycoprotein (HRG) redirects M2 to M1. We hypothesized that single nucleotide polymorphisms (SNPs) in CCL2 and HRG may predict clinical outcome in mCRC pts treated with anti-VEGF drug in combination with chemotherapy. Methods: This study enrolled 4 pts cohorts treated with antibody drug plus FOLFIRI in prospective trials, A: KRAS exon 2 wild-type (KRAS wt) pts (n=84), B: mutant-type pts (n=89) from FOLFIRI-arm of TRIBE trial (NCT00719797), C: bev-arm (n=295), D: cetuximab-arm (n=297), served as negative control arm, from KRAS wt pts of FIRE3 trial (NCT00433927). Functionally significant SNPs, CCL2 rs4586, HRG rs9898, and HRGrs2228243, were analyzed by PCR-based direct sequencing for associations with response rate (RR), progression-free survival (PFS), and overall survival (OS) by uni- and multivariable analyses. Results: The minor G allele of HRG rs2228243 was significantly associated with better PFS, but not RR and OS, than the A/A genotype in both uni- and multivariable analyses (10.8 vs 9.3 months. HR: 0.62, p=0.048; HR: 0.57, p=0.040, respectively) in the cohort B while it was not associated in the other KRAS wt cohorts. In the cohort C, the minor C allele of CCL2 rs4586 correlated with significantly shorter OS, but not RR and PFS, in both uni- and multivariable analyses (22.3 vs 28.4 months. HR: 1.61, p=0.003; HR: 1.63, p=0.004, respectively). No significant association of CCL2 rs4586 was seen in the other cohorts although pts with the C allele of CCL2rs4586 had a negative marginal significant association in PFS and a shorter OS than pts with the T/T genotype (22.0 vs 30.8 months) in the cohort A. Conclusions: Our study provides evidence that SNPs in CCL2 and HRG may serve as a predictive or prognostic marker in mCRC pts treated with bev plus FOLFIRI. Our results also suggest that the impact of the SNPs on outcome may differ according to KRAS status. Prospective validation of this study is warranted.