Background: Nucleotide excision repair (NER) is known as part of the DNA damage response (DDR) against platinum-induced DNA damage. Polymorphisms in miRNA binding sites of replication protein A (RPA2) and General Transcription Factor IIH Subunit 1 (GTF2H1) genes in NER pathway have shown to correlate with colorectal cancer risk. We tested whether the NER-related single nucleotide polymorphisms (SNPs) predict oxaliplatin efficacy in FOLFOXIRI regimen in patients (pts) with metastatic colorectal cancer (mCRC). Methods: Genomic DNA was extracted from 457 blood samples of mCRC pts enrolled in the TRIBE trial: 230 pts received first-line (1L) FOLFOXIRI plus bevacizumab (discovery cohort: median age, 60 yrs; median follow-up, 46.6 mos); and 227 pts received 1L FOLFIRI plus bevacizumab (control cohort: median age, 60 yrs; median follow-up, 49.0 mos). SNPs were analyzed by PCR-based direct sequencing. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier curves, log-rank test, and Cox proportional hazards regression. Results: In KRAS wild-type population among the discovery cohort, the C/C variant in RPA2 rs7356 was associated with shorter PFS and OS than any T allele (9.1 vs 13.3 mos, HR 2.32, 95%CI: 1.07-5.03, P= 0.020; 20.8 vs 37.1 mos, HR 1.94, 95%CI: 0.94-3.99, P= 0.059). Any C allele in GTF2H1 rs4596 was associated with shorter PFS than the G/G variant (10.8 vs 13.3 mos, HR1.64, 95%CI: 0.95-2.81, P= 0.045). In multivariable analysis, RPA2 rs7356 remained significant for PFS and OS (HR 2.97, 95%CI: 1.27-6.94, P= 0.012; HR 2.58, 95%CI: 1.19-5.58, P= 0.016). In all population of the discovery cohort, pts with any GTF2H1 rs4596 C allele had remarkably shorter PFS and OS than those with the G/G variant (11.3 vs 13.2 mos, HR 1.32, P= 0.087; 28.6 vs 34.3 mos, HR 1.36, P= 0.076). The findings remained in multivariable analysis. These findings were not confirmed in the control cohort. Conclusions: We suggest that miRNA binding sites of NER-related genes regulate DDR for oxaliplatin-related DNA damage. Germline RPA2 and GTF2H1 polymorphisms may predict oxaliplatin efficacy in mCRC pts.