Genetic factors may be of importance in determining inter-individual susceptibility to alcoholic liver disease (ALD). Among the candidate genes which have been considered to be important are those which code for enzymes involved in alcohol metabolism. Cytochrome P4502E1 (CYP2E1) metabolizes alcohol to acetaldehyde and the hydroxyethyl radical, and is also inducible by alcohol. A Rsa I restriction fragment length polymorphism (RFLP) in the 5'-flanking region of the CYP2E1 gene has been identified by other investigators, studies showing that the mutant allele (termed c2) shows greater transcriptional activity, higher protein levels and increased activity compared with the wild-type allele (c1). We have used PCR-RFLP analysis to determine whether the frequency of these alleles differed in 95 Caucasian patients with ALD compared with 205 control subjects (comprising 58 alcoholics with no liver disease, 47 patients with non-alcoholic liver disease and 100 healthy volunteers). In controls, the frequency (0.024) of the c2 allele was similar to that previously reported in other Caucasian populations. The c2 allele frequency in patients with ALD (0.1), however, was significantly (p = 0.0003; odds ratio (OR) 4.5, 95% CI 1.9-10.9) higher than in control subjects. The findings indicate that Caucasians carrying the Rsa I c2 allele of the CYP2E1 gene may be at higher risk of developing ALD if they abuse alcohol.