Objective To investigate the relationship of alpha fetoprotein (AFP) with activation of hepatic progenitor cells in hepatocellular carcinoma (HCC) and the prognosis of HCC patients. Methods The clinical data of 92 HCC patients who received curative hepatectomy were retrospectively analyzed. The patients included 76 males and 16 females, with a median age of 51 (ranging 25-72) years. Expression of AFP and CK19 protein was immunohistochemically stained and quantified. Kaplan-Meier survival analysis was used to observe the influence of AFP expression on postoperative survival of patients. Cochran-armitage trend test was used to analyse the association of AFP expression with activation of progenitor cells (CK19 staining). Results Patients with high AFP expression had a significantly shorter survival than those with low AFP expression (P=0.021). The activation score of hepatic progenitor cells was positively correlated with serum AFP concentration (P=0.046) and AFP expression in tumor tissues (P<0.001). Conclusion AFP expression in HCC tissue predicts a poor prognosis. AFP is closely associated with activation of hepatic progenitor cells.