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Background An increasing number of studies support cancer stem cells as the reason for chemoresistance to sorafenib therapy in hepatocellular carcinoma (HCC), but the mechanism is still unclear. In this study, the mechanism of sorafenib resistance in cancer stem cells was examined by in vitro experiments and xenograft mouse model. Methods The expression of cancer stem cell markers in the Chang liver cell line and PLC/PRF/5 and HepG2 hepatoma cell lines were compared by immunoblot assay before and after sorafenib treatment in vitro. As a xenograft mouse model, subcutaneous injection of hepatoma cells followed by sorafenib therapy was performed in NU/NU mice. The effects of sorafenib therapy on tumor growth and cancer stem cell markers were studied. Angiogenesis associated with cancer stem cells was studied by immunoblot and immunohistochemistry assay. Results The expression of cancer stem cell markers was higher in PLC/PRF/5 and HepG2 cells than Chang liver cells, indicating that these hepatoma cells had more stemness-related characteristics. The cancer stem cell markers were upregulated in the hepatoma cell lines following sorafenib treatment in vitro. In the xenograft model, tumors from PLC/PRF/5 and HepG2 cells with high E-cadherin expression were more resistance to sorafenib therapy. However, the expression of cancer stem cell markers was not significantly different after sorafenib therapy in these tumors. Furthermore, we found that sorafenib therapy induced angiogenesis within tumors from high E-cadherin expressing hepatoma cells. Conclusion The mechanism of chemoresistance in sorafenib therapy in HCC may be the tumor angiogenesis associated with high E-cadherin expression in cancer stem cells.