ABSTRACT—Aims and Methods: Proliferat bile ductules are classifiable histologically into typical and atypical types. To clarify their histogenesis and regulation, we examined their phenotype, proliferating and degrading characteristics, using liver sections from 58 patients with various hepatobiliary diseases. Results: Typical ductules were found in all cases. Atypical ductules were also frequently found in extrahepatic biliary obstruction (EBO), chronic hepatitis (CH), as well as in primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Typical ductules completely expressed biliary-type cytokeratins, while atypical ductules lacked complete biliary-type cytokeratins and often connected with periportal hepatocytes. Proliferative indices of typical ductules in diseased livers were higher than those in normal livers, while those of atypical ductules were low in PBC and PSC and high in EBO and CH. Apoptosis was detected in typical and atypical ductules. Perforin was preferably expressed on typical and atypical ductules, compared with CD95. Conclusions: These findings suggest that typical ductules reflect active proliferation of preexisting ductules. Atypical ductules might be classifiable into two categories: those in PBC and PSC primarily reflect ductular transformation (metaplasia) of periportal hepatocytes, while those in EBO and CH reflect active proliferation and transformation of hepatocytes. Apoptosis via perforin/granzyme B pathway may be involved in the maintenance of homeostasis in ductular proliferation as degrading fraction.