We examined the expression of Lewis antigens, particularly Lewis Y, on the intrahepatic biliary epithelial cells in normal livers and various hepatobiliary diseases with immunohistochemical and immunoelectron microscopic methods. In normal livers, Lewis Y was consistently and generally negative in the bile ductules and small bile ducts, respectively. This antigen was frequently and strongly expressed on these ducts and ductules showing variable pathological changes such as necroinflammation and proliferation in a majority of hepatobiliary diseases independent on their etiology, whereas a majority of normal-appearing bile ducts and ductules in these pathological conditions were negative. Immunoelectron microscopically, gold particles suggesting the presence of Lewis Y were demonstrated on microvilli facing the biliary lumen, lateral cell membranes, secretory granules and Golgi apparatus of abnormal biliary epithelial cells in various hepatobiliary diseases. These data suggest that neoexpression of Lewis Y antigen is a highly sensitive, nonspecific phenotypic change of carbohydrate residues occurring in the abnormal biliary epithelial cells in various hepatobiliary diseases. (Hepatology 1994;19:138–144).