A variety of environmental factors were identified to be associated with the risk of esophageal cancer. The variation in capacity of DNA repair might influence environmental chemical-associated carcinogenesis. We hypothesized that the polymorphic XRCCI genes might modify cancer susceptibility of the esophagus. To investigate the effect of XRCCI genetic polymorphisms an codons 194, 280 and 399, we evaluated data from 105 patients of esophageal squamous cell carcinoma and 264 healthy controls, matching with age (+/-3 years), gender and ethnicity, The distribution of the 3 genotypes were not significantly different among patients and controls, However, among alcohol drinkers, the XRCCI399 Arg/Arg genotype was move frequently found in patients with esophageal cancer. After adjustment with other environmental confounders, the OR for the genotype of XRCCI399 Arg/Arg was 2.78 (95% CI = 1.15-6.67) as compared with the XRCCI399 Arg/Gln and XRCCI399 Gln/Gln genotypes in the alcohol drinkers. Similar trends were observed among cigarette smokers and areca chewers. However, they did not reach a statistical significance. Our findings suggest that the polymorphic XRCCI genes might modify the risk of alcohol-associated esophageal cancers. (C) 2001 Wiley-Liss, Inc.