Autosomal recessive polycystic kidney disease (ARPKD) is characterized by biliary and renal lesions that produce significant morbidity and mortality. The biliary ductual ectasia and hepatic portal fibrosis associated with ARPKD have not been well studied even though such lesions markedly affect the clinical course of patients after renal replacement therapy such as dialysis or transplantation. Here we describe the generation of a new mouse model to study the hepatic lesions associated with polycystic kidney disease. This model was generated by differentially rescuing the renal pathology in the orpk mutant mouse that displays a hepatorenal pathology that is similar to that seen in human patients with ARPKD. This was accomplished by expressing, as a transgene in the mutant animals, the cloned wild-type version of the gene associated with the mutant locus in this line of mice. Although renal function in the rescue animals is normal, the liver still exhibits biliary and ductular hyperplasia along with varying degrees of hepatic portal fibrosis that is indistinguishable from that in the mutant animals. Most important, the rescue animals survive significantly longer than mutants and will permit a more detailed analysis of the clinical and cellular pathophysiology of the hepatic defect associated with this disease.