In both primary sclerosing cholangitis and primary biliary cirrhosis it is supposed that immunological mechanisms are involved in the progressive destruction of the bile ducts. The aberrant expression of human leukocyte antigen-DR in the bile ducts of patients with these disorders enables the biliary epithelium to present putative antigens to the surrounding lymphocytes; however, no such antigen has been identified. Heat-shock proteins have been implicated in the pathogenesis of various immunological destructive disorders. Liver biopsy specimens from patients with primary biliary cirrhosis (n = 10) and primary sclerosing cholangitis (n = 13) were compared with those from patients with chronic hepatitis C infection (n = 5) and alcoholic cirrhosis (n = 4) and from normal controls (n = 6). Liver sections were investigated by means of immunohistochemical study using a mouse monoclonal antibody, ML30, directed against the 65-kD heat-shock protein of Mycobacterium, with monoclonal antibody against human leukocyte antigen-DR and with the monoclonal antibody Identi-Tr TCR δ1, which recognizes a determinant on the δ-chain of the γ/δ form of the human T-cell receptor. Human leukocyte antigen-DR expression was found on the biliary epithelium of all primary sclerosing cholangitis and primary biliary cirrhosis patients but not on bile ducts from patients with alcoholic cirrhosis or chronic hepatitis C infection or those from normal controls. The biliary epithelium reacted with ML30 in 9 of 10 primary biliary cirrhosis patients and in all primary sclerosing cholangitis patients. Two different patterns of epithelial staining were observed: a perinuclear pattern and intense staining in the apical part of the cell cytoplasm, as demonstrated with confocal laser scanning microscopy. In the group of patients with chronic hepatitis C infection and alcoholic cirrhosis, ML30 reactivity was less extensive and was present only around the nuclei of bile duct cells. None of the bile ducts in the normal livers reacted with ML30. Staining with ML30 could not be correlated with the histological or clinical staging of the patients. The number and distribution of γ/δ T cells did not differ between the normal liver specimens and the various patient groups. Whether the finding of an induced expression of heat-shock protein in the secretory part of the biliary epithelium in primary biliary cirrhosis and primary sclerosing cholangitis will imply that the heat-shock proteins may act as an immune target recognized by the T cells surrounding the bile ducts in primary biliary cirrhosis and primary sclerosing cholangitis must be elucidated in further studies. (HEPATOLOGY 1993;18:298–303).