To evaluate contribution of polymorphisms of the XRCC1 gene to the risk of colorectal cancer, we conducted a case-control study of 209 colorectal cancer cases and 209 age- and gender-matched controls in the Korean population. We tested the hypothesis by constructing allele combinations with known SNP. Allelic variants of the XRCC1 gene at codons 194, 280 and 399 were analyzed in lymphocyte DNA by PCR-RFLP. We observed an increased risk of colorectal cancer associated with the 399Gln allele. The odds ratio (OR) was 1.61 (95% confidence interval [CI] 1.09-2.39) for the 399Gln allele. When combined allele-specific OR were calculated after estimating frequencies, 3 common allele combinations were found to be associated with an increased risk of colorectal cancer. The OR for the 194Trp-280Arg-399Arg was 1.48 (95% CI = 1.06-2.07) using 194Arg-280Arg-399Arg as the reference. The OR for the 194Arg-280His-399Arg and the 194Arg-280Arg-399Gln were 1.78 (95% CI = 1.09-2.89) and 1.78 (95% CI = 1.23-2.59), respectively. Analysis after controlling for smoking, exercise and dietary habits indicated that alcohol consumption (> or =80 g/week) is a significant risk factor of colorectal cancer (OR = 2.60, 95% CI = 1.46-4.62). An increased risk for colorectal cancer was identified in alcohol drinkers with the risky allele combinations. Our results suggest that polymorphisms in the XRCC1 genes may contribute to colorectal cancer susceptibility, and some evidence was obtained of a genetic modification for the relationship between alcohol intake and colorectal cancer.