Several hereditary syndromes characterized by defective DNA repair are associated with high risk of colorectal cancer (CRC). To explore whether common polymorphisms in DNA repair genes affect risk and prognosis of CRC, we evaluated the association between single nucleotide polymorphisms (SNPs) in XPG, XPC, and WRN gene and susceptibility of CRC, and clinical outcomes in a population-based case-control study. A total of 890 CRC cases and 910 controls recruited into the study provided a biologic sample. Individuals with variant genotypes of XPC Ala499Val appeared to be associated with the increased risk of CRC. WRN Cys1367Arg variants carriers showed an increased susceptibility for CRC. More importantly, the risk of CRC increased further in a combined analysis of multiple polymorphisms. Furthermore, stratified analyses revealed that XPG Arg1104His polymorphism was associated with tumor differentiation of CRC patients (P = 0.043). Log-rank test and adjusted multivariate Cox regression analysis verified that XPG Arg1104His variants were associated with a longer disease-free survival (DFS) [CG genotype: adjusted HR (95% confidence interval (CI)) = 0.163 (0.107-0.248), P < 0.001; CC genotype: adjusted HR (95% CI) = 0.333 (0.235-0.470), P < 0.001; CG/CC genotype: adjusted HR (95% CI) = 0.333 (0.235-0.470)] in patients with oxaliplatin-based chemotherapy (N = 718). Moreover, XPC Ala499Val CT genotype showed a significant impact on DFS [CC genotype: adjusted HR (95% CI) = 0.691 (0.528-0.904), P = 0.007; CT/CC genotype: adjusted HR (95% CI) = 0.602 (0.389-0.934), P = 0.024]. However, no correlation was found between WRN Cys1367Arg polymorphism and prognosis in CRC patients. Our findings will add to the literature on the impact of genetic variation in DNA repair genes involved in susceptibility for CRC and therapeutic outcomes in response to oxaliplatin-based chemotherapy.