Twin studies in Caucasians suggest that susceptibility to alcoholic liver disease is, in part, genetically determined. Because most of the deleterious effects of alcohol are caused by its metabolism, attention has focused upon genes encoding ethanol metabolizing enzymes. Caucasians are polymorphic at only two of these gene loci--cytochrome P450 2E1 (CYP2E1) and alcohol dehydrogenase 3 (ADH3). We examined the frequency of the RsaI polymorphism of CYP2E1 and ADH3 genotype in 264 patients with alcoholic liver disease and 121 local control individuals. There was a non-significant excess of the rare c2 CYP2E1 allele in patients with advanced liver disease compared with control individuals/patients with steatosis only (0.029 versus 0.017/0.00). However, patients with the c2 allele presented at a younger age compared with those with the wild type c1 allele only (42.3 +/- 1.6 years versus 49.0 +/- 0.6 years; P = 0.001) with at least as advanced histology (93% cirrhotic versus 74%). Male patients had a higher frequency of the ADH3*2/*2 genotype (which encodes the less active gamma2 subunit) than control individuals [odds ratio (OR) 2.04 (1.11-3.76)], however, ADH3 genotype did not differ with histological stage or with age of presentation. Patients with advanced disease possessing the c2 allele had a significantly higher frequency of the ADH3*2/*2 genotype compared with c1 homozygotes [OR 3.71 (1.24-11.09)]. This study demonstrates that, although rare in Caucasians, possession of the mutant c2 allele of CYP2E1 increases the risk of alcoholic liver disease at a given level of cumulative alcohol consumption. This risk appears to be particularly manifest in individuals carrying the ADH3*2 allele, presumably reflecting increased metabolism of ethanol by CYP2E1. In the absence of the c2 allele, ADH3 genotype does not influence the risk of advanced alcoholic liver disease but, in males at least, may influence the risk of alcoholism.