This study is intended to establish the genotype patterns at the ADH2, ADH3, and ALDH2 loci using a large number of Japanese alcoholics (n = 655) and controls (n = 461) representative of the Japanese general population. It complements an earlier small study and establishes definitively the effects of combinations of the genetic variations of the ADH2 and ADH3 alleles as well as ALDH2, thus providing a precise estimate of the risk for alcoholism. In this study, the alleles ADH2(2), ADH3(1), and ALDH2(2) appeared less frequently in alcoholics than in the general population (p < 0.001). The ADH2(3) allele was not found among 200 alcoholics and 200 controls screened, suggesting that it does not exist in indigenous Japanese. The ADH2(1)/ADH2(2) polymorphism was in linkage disequilibrium with the ADH3(1)/ADH3(2) polymorphism. The haplotype frequencies of ADH2 and ADH3 genes were estimated in the Japanese general and alcoholic populations. Increased risk for alcoholism was shown in individuals with homozygous ALDH2(1) and the ADH2(1) allele (p < 0.001), but the relative risk was less than 1 in those with the homozygous ADH2(2). Japanese with ALDH2(1)/2(2) had a low risk in the presence of the ADH2(2) (p < 0.001), but the risk was significantly increased in those with the homozygous ADH2(1) allele (OR 2.0, 95% CI 1.0-4.3, p < 0.05). The ALDH2(2)/2(2) genotype was found in none of the alcoholics, suggesting that individuals with homozygous ALDH2(2) never become alcoholics.