A rabbit animal model of the human disease familial hypercholesterolemia (FH), which is the result of low density lipoprotein (LDL) receptor deficiency, was used to develop an in vivo approach to gene therapy based on recombinant adenoviruses. Recombinant, replication-defective adenoviruses expressing the lacZ gene under the control of different promoters were infused into the portal circulation of New Zealand White (NZW) rabbits. Expression of lacZ could be obtained in virtually all hepatocytes within 3 days post-infusion, but was undetectable by 3 weeks. This was not associated with liver pathology. An LDL receptor expressing adenovirus was constructed using the most active promoter and was infused into the portal vein of rabbits deficient in LDL receptor. Analysis of liver tissues harvested 3 days after virus infusion demonstrated human LDL receptor protein in the majority of hepatocytes that exceeded the levels found in human liver by at least 10-fold. Transgene expression was stable for 7-10 days and diminished to undetectable levels within 3 weeks. Infusion of LDL receptor expressing virus led to substantial reductions in serum cholesterol that returned to base line within 3 weeks; this acute reduction in serum cholesterol was associated with accumulations of lipid in hepatocytes. The development of neutralizing antibodies to the recombinant adenovirus markedly diminished the effectiveness of a second dose. These studies illustrate the advantages of recombinant adenoviruses for the treatment of liver metabolic diseases and define issues, such as viral genome instability and blocking immune response, that need to be overcome before the promise of this technology can be fully realized.