Many human cancers are caused by synthetic or natural chemical compounds in the environment. Esophageal squamous cell carcinoma has been reported to be epidemiologically associated with tobacco and alcohol consumption. We studied the association between genetic polymorphisms of tobacco- and alcohol-related metabolizing enzymes and esophageal squamous cell carcinoma susceptibility. We examined genetic polymorphisms of the CYPIA1, GSTM1, CYPIIE1, ADH2, and ALDH2 genes in 94 Japanese patients with esophageal squamous cell carcinoma and 70 unrelated healthy Japanese persons. There were no significant differences between healthy controls and patients with esophageal cancer in the polymorphisms of the CYPIA1, GSTM1, and CYPIIE1 genes. On the other hand, there were significant differences in the ADH2 and ALDH2 polymorphisms between healthy controls and esophageal cancer patients. The ADH2(1)/ADH2(1) and ALDH2(1)/ALDH2(2) genotypes were independently and significantly higher in esophageal cancer patients than in healthy controls. Furthermore, persons with the combined genotypes ADH2(1)/ADH2(1) and ALDH2(1)/ALDH2(2) were at extraordinarily high risk for esophageal squamous cell carcinoma, with an odds ratio of 17.9 (p < 0.001). Thus polymorphisms of alcohol-metabolizing enzymes, that is, ADH2 and ALDH2, may be useful for screening patients at high risk for esophageal cancer, which might facilitate clarification of esophageal tumorigenesis and prevention of esophageal cancer.