Abstract: Objective To explore the roles of (Golgi protein 73, GP73) and PI3K/Akt pathway in the sorafenib resistant mechanism in patients with hepatocellular carcinoma. Methods MTT assay was used to detect the inhibitory rate of sorafenib on cell viability. Sorafenib resistant Hep G2 cell was established by long term and low dose sorafinib incubation.The cell morphologic change was observed under an inverted phase contrast microscope. GP73 were overexpressed and knocked down by plasmid transfection in sorafinib resistant Hep G2 cell, and the effect of GP73 on sensitivity of sorafinib was detected. GP73, EMT markers and PI3K/Akt signal pathway molecules proteins were detected by Western blot in sorafinib resistant and non-resistant cells. Results Different concentrations of sorafenib on Bel-7404, SK-Hep-1 and Hep G2 cells all had inhibitory effects. Long term and low dose of sorafinib stimulated the morphologic change of cells to long spindle shape. Overexpression of GP73 decreased the sensitivity of sorafenib; knockdown of GP73 increased drug sensitivity. Compared with non-resistant cell, GP73, N-cadherin and Vimentin expression were increased, E-cadherin was decreased (all P < 0.05). Besides, GP73, PI3 K and p-Akt levels were also elevated in resistant cell. Conclusion The up-regulation of GP73 and activated PI3K/Akt pathway, which promoted EMT, may be the possible mechanism of sorafenib resistance of HCC.