Purpose: Sorafenib is a chemotherapy drug approved for the treatment of HCC in China. Digitoxin is a cardiotonic drug whose anticancer effect has been found in multiple cancer types, but not in HCC. The aim of this study is to evaluate the combinational effect of Sorafenib and digitoxin towards HCC and investigate the relevant molecular mechanisms. Methods: The proliferation, cell death and migration of HCC cell lines HepG2 and BEL-7402 were examined using MTT, AO/EB assay and scratch wound healing assay respectively. The expression changes in phospho-ERK, HIF-1, HIF-2 and VEGF were measured using western blotting. Results: Digitoxin synergized with Sorafenib to inhibit cell viability, but not migration. In downstream signalling pathways, the activity of ERK was synergistically suppressed by the combination of Sorafenib and digitoxin in both HepG2 and BEL-7402 cells. Moreover, the expression of HIF-1, HIF-2 and VEGF was also synergistically down-regulated by the combinational treatment. Conclusion: Sorafenib synergized with digitoxin to inhibit HCC cell viability, but not migration, which is probably mediated through the suppression of ERK and hypoxia signalling.