The canals of Hering (CoH), converging from the hepatic lobule onto the portal tract, connect bile canaliculi to the interlobular bile ducts, and represent the most proximal portion of the bile drainage pathway with a cholangiocyte lining. In this study we sought to ascertain whether this proximal pathway is involved by the disease process in primary biliary cirrhosis (PBC), which uniformly affects small bile ducts while sparing medium- and large-sized ducts. Ten biopsy specimens with early-stage PBC were compared with 6 normal control livers. Adjacent 4-micron-thick sections of routinely processed, formalin-fixed tissue were immunostained for CK19 and HLA-DR. Each terminal portal tract was assigned a stage: 0, normal; 1, bile duct damage or loss; 2, bile ductular proliferation; or 3, periportal fibrosis. The ratio of the number of CoH to number of portal tracts (i.e., the c/p ratio) was calculated for the control biopsies and individual portal tracts at each stage of PBC. The numbers of CoH were decreased in all stages of PBC (P <0.0001), with the fewest found around portal tracts at stages 0 and 1 and the most around portal tracts at stages 2 and 3, but never at normal levels. HLA-DR was expressed focally on bile ducts and CoH in PBC, but was absent in normal controls. We conclude that CoH are destroyed in PBC in concert with the destruction of small bile ducts. This destruction appears to be an early event, because CoH numbers are lowest around stage 0 portal tracts, which still contain normal bile ducts.