Background: CCL5/CCR5 pathway is known to mediate VEGF-A production. A recent study reported that serum VEGF-A and CCL5 levels predict efficacy of regorafenib in metastatic colorectal cancer (mCRC). We tested whether genetic polymorphisms in the CCL5/CCR5 pathway are associated with outcomes in patients with refractory mCRC treated with regorafenib. Methods: We analyzed genomic DNA extracted from 229 samples of two cohorts receiving regorafenib: an evaluation cohort of 79 patients (median age 62 years, male 47%, median follow-up time 15.3 months); and a validation cohort of 150 patients (median age 62 years, male 54%, median follow-up time 36.4 months). Nine single nucleotide polymorphisms (SNPs) of genes in CCL5/CCR5 pathway (CCL5, CCR5, PRCKD, CCL3, CCL4, KLF13, HIF1A) were analyzed by PCR-based direct sequencing. Associations between SNPs with progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier curves and log-rank test. Multivariable analyses including SNP and baseline characteristics were performed using the Cox proportional hazard regression model. Results: In the evaluation cohort, patients with any A allele in CCL4 rs1634517 had a significant shorter PFS compared to those with the C/C variant (2.0 vs. 2.5 months, HR 1.54, P= 0.043). Patients carrying any A allele in CCL3 rs1130371 had marginally significant shorter PFS (2.0 vs. 2.5 months, HR 1.48, P= 0.064) than those with the G/G variant. In the validation cohort, Patients with any A allele in CCL4 rs1634517 had a shorter PFS (1.8 vs. 2.3 months, HR 1.74, P= 0.001) and OS (4.4 vs. 7.9 months, HR 1.65, P= 0.004) compared to those with the C/C variant. It remained significant in multivariable analysis for PFS and OS (P= 0.012 and 0.041). Patients carrying any A allele in CCL3 rs1130371 had a shorter PFS (1.8 vs. 2.3 months, HR 1.66, P= 0.002) and OS (4.4 vs. 7.9 months, HR 1.65, P= 0.004) than those with the G/G variant; these effects were significant in multivariable model (PFS: P= 0.027; OS: P= 0.047). Conclusions: Genetic variants in the CCL5/CCR5 pathway, CCL4 rs1634517 and CCL3 rs1130371, may serve as predictive and prognostic markers in refractory mCRC patients receiving regorafenib.