Alcohol dehydrogenase (ADH), aldehyde dehydrognase (ALDH), and P450IIE1 are the primary enzymes that catalyze the conversion of ethanol to acetaldehyde and then to acetate. Genetic polymorphisms have been reported in ADH2, ADH3, ALDH2, and the 5′-flanking region of P450IIEI. In this study, we used multivariate analysis to determine which genetic polymorphisms in alcohol metabolizing enzymes were independently associated with the development of alcoholic cirrhosis. Thirty-four noncirrhotic alcoholic patients, including 27 with fatty liver and 7 with nonspecific changes, and 46 patients with alcoholic liver cirrhosis were studied. Restriction fragment length polymorphisms (RFLPs) in the ADH2 and P450IIE1 genes were detected by digestion of polymerase chain reaction (PCR)-amplified DNA with MaeIII and RsaI, respectively. In the ALDH2 gene, RFLPs were detected by differences in the MboII site after PCR amplification. By multivariate analysis of four significant factors including total alcohol intake, ADH, ALDH, and P450IIE1 using the multiple logistic regression model, genotype ADH22/ADH22 (P = .029) and genotype c1/c1 of P450IIE1 (P = .013) were found to be independently associated with alcoholic cirrhosis. The odds ratios for ADH22/ADH22 genotype and the type A genotype of P450IIE1 (c1/c1) were 4.600 and 4.006, respectively. These results suggest that ADH2 and P450IIE1 gene polymorphisms may be independently associated with the development of alcoholic liver cirrhosis in Japan. (HEPATOLOGY 1995; 22:1136–1142.).