Epithelial cell adhesion molecule (EpCAM) is a surface marker on human hepatic stem/ progenitor cells that is reported as absent on mature hepatocytes. However, it has also been noted that in cirrhotic livers of diverse causes, many hepatocytes have EpCAM surface expression; this may represent aberrant EpCAM expression in injured hepatocytes or, as we now hypothesize, persistence of EpCAM in hepatocytes that have recently derived from hepatobiliary progenitors. To evaluate this concept, we investigated patterns of EpCAM expression in hepatobiliary cell compartments of liver biopsy specimens from patients with all stages of chronic hepatitis B and C, studying proliferation, senescence and telomere lengths. We found that EpCAM(1) hepatocytes were rare in early stages of disease, became increasingly prominent in later stages in parallel with the emergence of ductular reactions, and were consistently arrayed around the periphery of cords of keratin 19(1) hepatobiliary cells of the ductular reaction, with which they shared EpCAM expression. Proliferating cell nuclear antigen (proliferation marker) and p21 (senescence marker) were both higher in hepatocytes in cirrhosis than in normal livers, but ductular reaction hepatobiliary cells had the highest proliferation rate, in keeping with being stem/progenitor cell-derived transit amplifying cells. Telomere lengths in EpCAM(1) hepatocytes in cirrhosis were higher than EpCAM(2) hepatocytes (P < 0.046), and relatively shorter than those in the corresponding ductular reaction hepatobiliary cells (P 5 0.057). Conclusion: These morphologic, topographic, immunophenotypic, and molecular data support the concept that EpCAM(1) hepatocytes in chronic viral hepatitis are recent progeny of the hepatobiliary stem/progenitor cell compartment through intermediates of the transit amplifying, ductular reaction hepatobiliary cells. (HEPATOLOGY 2011;53:964-973) T here is a growing consensus that some contribution to hepatocyte mass derives from intrahepatic, hepatobiliary stem cells and that the contribution depends on presence of injury, its form, and its degree. [1][2][3][4][5][6][7][8] Support for this concept is found in animal models, often employing a two-hit experimental method in which there is poisoning of hepatocytes to inhibit their replication (e.g., 2-acetylaminofluorene) Abbreviations: CHB, chronic hepatitis B; CHC, chronic hepatitis C; EpCAM, epithelial cell adhesion molecule; K, keratin; PCNA, proliferating cell nuclear antigen.