Although drinking alcohol is an established esophageal cancer risk factor, the mechanisms by which alcohol induces this high-mortality rate cancer are not clear. To help elucidate this problem and develop an implementable preventive strategy, this genetic epidemiological study focused on aldehyde dehydrogenase 2 (ALDH2), the key enzyme for elimination of acetaldehyde generated by alcohol consumption. This enzyme is polymorphic; its mutant allele, ALDH2*2, which leads to the enzyme inactivity, is prevalent in Orientals. This Japanese case-control study of ALDH2-related risk for esophageal squamous cell carcinoma included alcoholics (40 cases and 55 controls) and nonalcoholic drinkers (29 cases and 28 controls). The analysis of the results of genotyping these subjects showed that the increased risk for esophageal cancer in those with one ALDH2*2 allele was substantially higher in both alcoholics (odds ratio = 7.6; 95% confidence interval = 2.8-20.7) and nonalcoholic drinkers (odds ratio = 12.1; 95% confidence interval = 3.4-42.8). The results strongly suggest that because persons who have this mutant ALDH2*2 allele have a high concentration of blood acetaldehyde after drinking alcohol, acetaldehyde (a recognized animal carcinogen) plays a pivotal role in the pathogenesis of alcohol-related esophageal cancer in humans. These results suggest that to help lower their risk for esophageal cancer, persons with the ALDH2*2 allele should be encouraged to reduce their consumption of alcoholic beverages.