Background: Liver dysfunction is a common manifestation of cystic fibrosis (CF), a disease caused by mutations affecting the CF transmembrane conductance regulator (CFTR). The aim of this study was to examine the distribution and role of CFTR in liver. Methods: CFTR messenger RNA was detected in cryosections of human liver by in situ hybridization. CFTR immunoreactivity was detected using antibodies raised against two CFTR peptides. Results: The predominant site of CFTR messenger RNA and immunoreactivity in liver is the intrahepatic bile duct. CFTR is not detected in hepatocytes of normal liver or in livers exhibiting bile duct proliferation. Within bile duct cells, CFTR is localized at or near the apical plasma membrane. Conclusions: The apical localization of CFTR in bile duct cells suggests a model explaining how the CFTR-associated Cl⁻ channel contributes to normal biliary secretion. This model suggests that if CFTR expression could be promoted in intrahepatic duct cells by somatic gene therapy, this might prevent the occurrence of liver disease in CF.