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Summary Aim To evaluate the prognostic significance of the epithelial cell adhesion molecule (EpCAM) expression in HCC, the relationship between EpCAM with ductular reactions and other clinical features. Methods From 2001 to 2003, 106 HCC patients who underwent curative resection in Eastern Hepatobiliary Hospital were enrolled. The expression of EpCAM in tumoral tissues and ductular reactions in paired non-tumoral tissues was assessed by immunohistochemistry. EpCAM was evaluated with prognosis, ductular reactions and other clinical variables. Results HCC expressing high level of EpCAM showed more aggressively than usual progressed HCC. High EpCAM expression was associated with poor overall survival and recurrence free survival. (P = 0.0005, 0.0019, respectively). A close association was found between tumoral EpCAM expression and peritumoral ductular reactions. Patients with high level of ductular reactions tended to have higher EpCAM expression than those with low level (P = 0.016). Conclusion HCC stratification by EpCAM may reflect different prognosis. EpCAM expression correlated with ductular reactions may be a result of unregulated activation and differentiation blockage of progenitor cells.