The activity of drug-metabolizing enzymes was compared in liver, kidneys and lungs of rats given single or repetitive fluke infections. Fascioliasis was induced by oral administration of 20 metacercariae of F. hepatica to rats, either 6, or 12 and 6, or 12, 9 and 6 weeks before sacrifice. In the liver of mono-infected rats, significant reductions (24-67%) were observed in microsomal content of cytochrome P450 and all P450-dependent monooxygenases investigated. Conjugations to glutathione or acetate were lowered by 34-50% in these animals. In multiply infected animals, a majority of specific enzymatic activities were unchanged, while some monooxygenase activities such as aminopyrine demethylation or benzo(a)pyrene hydroxylation were increased by 26-76% in the liver of tri-infected rats. A renal compensatory process occurred in all infected groups, since cytochrome P450, benzphetamine demethylation and glutathione conjugation were significantly increased. By contrast, dealkylation of benzphetamine and pentoxyresorufin were decreased in the lungs of monoinfected rats. The development of parasite resistance would account for the recovery of liver drug metabolizing capabilities in multi-infected animals.