We have studied by use of PCR and XbaI and EcoRI restriction-fragment-length polymorphism whether mutations at the polymorphic CYP2D6 (debrisoquine hydroxylase) gene locus are associated with liver cancer. The frequency of CYP2D6 genes containing inactivating mutations was lower among 75 liver cancer patients than 200 healthy controls, and 40 cirrhotic subjects that did not develop liver cancer (frequency for carriers of two or more functional genes was 95% vs 74% vs 78%, respectively). Subjects who were homozygous for functional CYP2D6 genes appear to be at higher risk of developing primary liver cancer (odds ratio 6.40 [95% Cl] 2.4-17.5).