Aldehyde dehydrogenase-2 (ALDH2) eliminates most of the acetaldehyde produced during alcohol metabolism. In some drinkers, a mutant ALDH2 allele contributes to diminished activity of the enzyme, dramatically increasing the risk for esophageal cancer. This study was designed to evaluate the ALDH2 gene polymorphism as a predictor of the development of cancers prevalent in Japanese alcoholics. We performed ALDH2 genotyping on lymphocyte DNA samples from Japanese alcoholic men (487 cancer-free; 237 with cancer, including 34 oropharyngolaryngeal, 87 esophageal, 58 stomach, 46 colon, 18 liver, 7 lung, 9 other sites, and 19 multiple primary cancers in two or three organs). The frequencies of the mutant ALDH2*2 allele were significantly higher in alcoholics with oropharyngolaryngeal (52.9%), esophageal (52.9%), stomach (22.4%), colon (21.7%) and esophageal cancer concomitant with oropharyngolaryngeal and/or stomach cancer (78.6%), than in cancer-free alcoholics (9.0%). After adjustment for age, daily alcohol consumption and amount of cigarette smoking, significantly increased risks (odds ratios) in the presence of the ALDH2 *2 allele were found for oropharyngolaryngeal (11.14), esophageal (12.50), stomach (3.49), colon (3.35), lung (8.20) and esophageal cancer concomitant with oropharyngolaryngeal and/or stomach cancer (54.20) but not for liver or other cancers. These results suggest a general role of acetaldehyde, a recognized animal carcinogen, in the development of human cancers.