OBJECTIVE： To study the mechanism of myocyte enhancer factor 2D （MEF2D） affecting the resistance of hepatoma carcinoma cells PLC to sorafenib. METHODS： The liver cancer drug resistance cell strain （PLC-DR3） of sorafenib were established， over expression Ad-MEF2D carrier infected liver cancer cell PLC （PLC-AdMEF2D） and CCK-8 assay was used to determine the proliferation of PLC， PLC-DR3 and PLC-AdMEF2D， and the half inhibitory concentration （IC50） of sorafenib on each cell was calculated. Western blot assay was used to detect the protein expression of MEF2D， ERK and p-ERK in PLC and PLC-DR3， the protein expression of MEF2D， ERK， p-ERK， MEK， p-MEK and SPRY4 in PLC-AdMEF2D. RT-PCR was adopted to detect the mRNA expression of MEF2D and SPRY4 in PLC and PLC-AdMEF2D. RESULTS： IC50 of sorafenib on PLC， PLC-DR3， PLC-AdMEF2D was （8.23±0.06），（21.80±0.06），（19.46±0.063） μmol/L. Compared with PLC， the IC50 of PLC-DR3 and PLC-AdMEF2D was increased significantly （P＜0.001）； the total expression of ERK in PLC-DR3 keep stale， while the protein expression of MEF2D and p-ERK was increased significantly （P＜0.001）； total expression of ERK and MEK in PLC-AdMEF2D kept stable， but the protein expression of p-ERK and p-MEK were increased significantly （P＜0.01）， the protein expression of SPRY4 was decreased significantly （P＜0.001）， while mRNA expression of SPRY4 was decreased significantly （P＜0.001）. CONCLUSIONS：  MEF2D can promote the generation and development of drug resistance of hepatoma carcinoma cells to sorafenib by inhibiting expression of SPRY4 and active of RAS/ERK pathway.