Autoantibodies reacting with the galactose-specific hepatic asialoglycoprotein receptor--a liver-specific component expressed on the surfaces of hepatocytes--are often found in patients with chronic active hepatitis of presumed autoimmune origin. As part of an investigation into whether these anti-asialoglycoprotein receptor antibodies might be involved in the development of periportal liver damage in chronic active hepatitis, livers of ether-anesthetized rats were perfused in situ with polyclonal guinea pig anti-rabbit asialoglycoprotein receptor or murine monoclonal anti-human galactose-specific hepatic asialoglycoprotein receptor antibodies in excess at less than 8 degrees C or, as a control, with guinea pig anti-human plasma protein antibodies or normal guinea pig serum. Rapid (1 min) antegrade (by way of portal vein) or retrograde (through hepatic veins by way of vena cava) perfusions were performed in a nonrecirculating (once-through) mode in Ca+(+)-free medium. Blocks of liver tissue were immediately snap-frozen and the distribution of the antibody examined in cryostat sections by using an avidin-biotin immunohistochemical technique. In all of the perfusions with anti-asialoglycoprotein receptor (six antegrade, seven retrograde), the antibodies were found to be prominently and almost exclusively deposited on liver cells in the periportal areas. No deposition of immunoglobulins was detected in livers perfused with the control guinea pig sera. The findings suggest that the asialoglycoprotein receptor is expressed at high density mainly on cells in zone 1 of the hepatic lobule, and this may have implications for the development of periportal liver damage in chronic active hepatitis.