We conducted a study to investigate the role of excision repair cross-complimentary group 1 gene (ERCC1)-xeroderma pigmentosum complementation group F (XPF) gene polymorphisms in response to chemotherapy and clinical outcome of gastric patients. Three SNPs in ERCC1 (rs11615, rs3212986, and rs2298881) and two SNPs in XPF (rs2276465 and rs6498486) were extracted using Tiangen DNA kit (Tiangen Biotech, Beijing, China) according to the manufacturer's instructions. The median follow-up time was 36.4 months, and ranged from 2-60 months. During the follow-up period, 112 patients died from gastric cancer. Individuals carrying ERCC1 rs11615 AA and XPF rs6498486 CC genotypes were associated with poorer response to chemotherapy when compared with wild-type genotype, with the ORs (95 % CI) of 0.48 (0.25-0.94) and 0.38 (0.14-1.00). In the Cox proportional hazards model, individuals carrying ERCC1 rs11615 GA and AA genotype had 1.91 and 2.66 risk of death when compared with those carrying GG genotype. Patients carrying the XPF rs6498486 AC and CC genotype were associate with 2.17 and 4.91-fold risk of death when compared with wild-type genotype. In conclusion, we found that ERCC1 rs11615 and XPF rs2276465 may substantially contribute to the future design of individualized cancer treatment in gastric cancer patients.