To evaluate the relationship of genetic polymorphisms of ERCC2 and ERCC4 genes, both involved in nucleotide excision repair (NER), and the risk of breast cancer, a hospital-based case-control study was conducted in Korea. Histologically confirmed breast cancer cases (n = 574) and controls (n = 502) with no present or previous history of cancer were recruited from three teaching hospitals in Seoul during 1995-2001. Information on selected characteristics was collected by interviewed questionnaire. ERCC2 Asp(312)Asn (G>A) was genotyped by single-base extension assay and ERCC4 Ser(835)Ser (T>C) by dynamic allele-specific hybridization system. Although no significant association was observed between the genetic polymorphisms and the risk of breast cancer, women with both ERCC2 A allele- and ERCC4 C allele-containing genotypes showed a 2.6-fold risk (95% CI: 1.02-6.48) of breast cancer compared to women concurrently carrying the ERCC2 GG and ERCC4 TT genotypes. The breast cancer risk increased as the number of "at risk" genotypes increased with a borderline significance (P for trend = 0.07). Interactive effect was also observed between ERCC4 genotype and body mass idnex (BMI) for the breast cancer risk; the ERCC4 C allele containing genotypes posed a 1.7-fold (95% CI: 0.96-2.93) breast cancer risk in obese women (BMI>25 kg/m(2)) with a borderline significance. Our finding suggests that the combined effect of ERCC2 Asp(312)Asn and ERCC4 Ser(835)Ser genotypes might be associated with breast cancer risk in Korean women.