To investigate the relationship among alcohol dehydrogenase-2 (ADH2) and aldehyde dehydrogenase-2 (ALDH2) genetic polymorphisms, alcohol consumption and the susceptibility to esophageal cancer in a Chinese population, we conducted a case-control study with 221 cases and 191 population-based controls in the Taixing city of Jiangsu Province of China. ADH2 and ALDH2 genotypes were examined using PCR and denaturing high-performance liquid chromatography. Alcohol drinkers with the ALDH2 A allele showed a significantly increased risk of esophageal cancer compared with drinkers with the ALDH2 G/G genotype (odds ratio (OR)=3.08, 95% confidence interval (CI): 1.65-5.78) or nondrinkers with any genotype (OR=3.05, 95% CI: 1.49-6.25). Drinkers with the ALDH2 A allele and a cumulative amount of alcohol consumption > or =2.5 (kg * years) were at a significantly higher risk of developing esophageal cancer (OR=11.93, 95% CI: 3.17-44.90) compared with individuals with ALDH2 G/G genotypes and a cumulative amount of alcohol consumption <2.5 (kg * years). A dose-dependent positive result was found between cumulative amount of alcohol consumption and risk of esophageal cancer in individuals carrying the ALDH2 A allele (P=0.023) and the homozygous ALDH2 G allele (P=0.047). Compared with individuals carrying both ALDH2 G/G and ADH2 A/A alleles and with a cumulative amount of alcohol consumption <2.5 (kg * years), drinkers carrying both ALDH2 A and ADH2 G alleles and with a cumulative amount of alcohol consumption > or =2.5 (kg * years) showed a significantly elevated risk of esophageal cancer (OR=53.15, 95% CI: 4.24-666.84). This result suggests that to help lower their risk for esophageal cancer, persons carrying the ALDH2 A allele should be encouraged to reduce their consumption of alcoholic beverages.