Abstract: Objective To explore the correlation between polymorphisms in the X-ray repair cross-complementing protein 1 (XRCC1) and ATP-binding cassette superfamily G member 2 (ABCG2) genes and the sensitivity to platinum-based chemotherapy in patients with advanced colorectal cancer (CRC). Methods A total of 75 patients with advanced CRC admitted to Pingyang Hospital Affiliated to Wenzhou Medical University between January 2021 and August 2022 were enrolled, all of them received platinum-based chemotherapy for 24 weeks. Before chemotherapy, polymorphisms of peripheral blood XRCC1-Rs25487 and ABCG2-Rs717620 were detected, and their relationship with 2-year overall survival rate was explored. The influencing factors of poor prognosis were analyzed by proportional hazards (Cox) regression model. Results The overall response rate to chemotherapy was 52.00% (39/75) among the 75 patients. In XRCC1-Rs25487 genotypes, sensitivity to platinum-based chemotherapy in AA genotype was lower than that in GG+GA genotype (P ＜ 0.05). In ABCG2-Rs717620 genotypes, sensitivity to platinum-based chemotherapy in TT genotype was lower than that in CC+CT genotype (P ＜ 0.05). Kaplan-Meier analysis showed that in XRCC1-Rs25487, median survival time of GA/GG genotype was longer than that of AA genotype. In ABCG2-Rs717620, median survival time of CC/CT genotype was longer than that of TT genotype (P ＜ 0.05). Multivariate Cox analysis showed that platinum-based chemotherapy response, AA genotype of XRCC1-Rs25487 and TT genotype of ABCG2-Rs717620 were independent influencing factors of 2-year overall survival rate in patients with advanced CRC after platinum-based chemotherapy (P ＜ 0.05). Conclusion Polymorphisms in the XRCC1 and ABCG2 genes are associated with sensitivity to platinum-based chemotherapy in patients with advanced CRC. XRCC1-Rs25487 GG/GA genotypes and ABCG2-Rs717620 CC/CT genotypes can provide better sensitivity to platinum-based chemotherapy and survival for patients with advanced CRC.