This study aimed to investigate whether single nucleotide polymorphisms (SNPs) in the promoter of the excision repair cross complementation group 5 (ERCC5) gene influences response to oxaliplatin-based chemotherapy. Eighty-three patients with cytologically or histologically confirmed advanced colorectal cancer (CRC), at least one measurable lesion and underwent oxaliplatin-based chemotherapy were studied. To this end, six polymorphisms (-1415C>T, -763A>G, -413C>T, +25A>G, +202C>T, +372C>T) in the ERCC5 promoter were selected for investigation. Genomic DNA was obtained from peripheral blood cells, and polymerase chain reaction-ligation detection reaction was used to analyze these SNPs. The chi(2) test or Fisher's exact test was then used to investigate the association between polymorphisms and chemotherapy response. Our results showed that the response rate among patients with the -763GG genotype (72.7%) was significantly higher than that of other genotypes (22.2% for AA genotype, p = 0.008 and 37.2% for AG genotype, p = 0.046 respectively). In addition, the response rate among patients with the +25AA genotype (75%) was significantly higher than that of other genotypes (24.1% for GG genotype, p = 0.004 and 35.7% for AG genotype, p = 0.022 respectively). Patients with the -763A/+25G haplotype had a higher risk of non-response to oxaliplatin chemotherapy compared to those carrying the -763G/+25A haplotype (OR 2.672, 95% CI 1.353-5.278, p = 0.004). However, no genetic variation was observed at site -413, and no significant association was found between the -1415C>T, +202C>T or +372C>T polymorphisms and chemotherapy response. Therefore, these data suggest that ERCC5 promoter polymorphisms at -763 and +25 may be important predictors of response to oxaliplatin chemotherapy.