Portal fibroblasts are newly discovered liver cells that may be of particular importance in biliary fibrosis. Recent data indicate that portal fibroblasts express NTPDase2, an ecto-nucleoside triphosphate diphosphohydrolase. Portal fibroblasts exist within the peri-portal regions of rat livers and express NTPDase2 adjacent to the basolateral side of intrahepatic bile ducts. Because extracellular nucleotides regulate secretion via activation of P2Y purinergic receptors, extracellular nucleotide hydrolysis via NTPDase2 makes NTPDase2 a potential regulator of bile ductular secretion. We propose that NTPDase2 expression may be altered in biliary fibrosis, especially in conditions in which bile duct epithelia are the target of disease. To test this hypothesis we have contrasted the distribution of NTPDase2 in normal and diseased liver states. Using confocal immunofluorescence, we assessed differences in expression of NTPDase2 in liver biopsy specimens from normal liver, primary biliary cirrhosis (PBC), and hepatitis C (HepC). We found that NTPDase2 was down regulated in the peri-portal regions of patients with PBC when compared to normal patients. Hepatitis C, however, showed NTPDase2 staining equal to or nearly equal to that of normal liver. The intermediate filament vimentin was down regulated in both PBC and Hep C when compared to normal liver. We conclude that NTPDase2 expression is down regulated in PBC but not Hep C, while vimentin is down regulated in both disease states when compared to normal liver.