Because alcoholic hepatitis and cirrhosis, well-known complications of alcohol abuse, do not occur in all alcoholics, genetic factors such as differences in alcohol-metabolizing enzymes may play a role in the development of alcoholic liver disease. Cytochrome P450IIE1 catalyzes the oxidation of ethanol, producing acetaldehyde and free radicals capable of reacting with and peroxidizing cell membranes. Polymorphisms have been identified in the 5'-flanking region of the P450IIE1 gene that may alter the transcriptional activity of the gene. In this study, we analyzed the P450IIE1 genotypes at the polymorphic PstI and RsaI restriction enzyme sites in 53 Caucasians with severe alcoholic liver disease to determine if there is an association between these polymorphisms and alcoholic liver disease. Subjects that tested positive for the hepatitis C virus were eliminated from the study. To identify the type A (homozygous for the c1 gene), type B (heterozygous for the c1 and c2 genes), and type C (homozygous for the c2 gene) genotypes at the P450IIE1 locus, DNA encompassing the polymorphisms was amplified by polymerase chain reaction, slot-blotted, and probed with allele-specific oligonucleotides. Allele frequencies for the c1 allele were 0.95 for alcoholics with severe liver disease, 0.95 for alcoholics without liver disease, and 0.98 for the general population. No differences in allele frequencies between alcoholic patients with severe liver disease and alcoholics without liver disease were observed.