Abstract: Objective：To investigate the effects of combination treatment of phloridzin and sorafenib on the energy metabolism and apoptosis of hepatocellular carcinoma cells. Methods：HepG2 cells were treated with sorafenib (5 μmol/L) and/or phloridzin (5 μmol/L) for 48 h, then the cell viability, glucose uptake, ATP content, caspase-3 activity, and apoptosis were analyzed. Results：Cell viability was inhibited in the sorafenib group compared with the control group(P<0.05); a more obvious inhibitory effect was found in the combined treatment group, and significant differences were found between the combined treatment group and all other groups (combined treatment group vs control group, sorafenib group, or phloridzin group; all P<0.05).The glucose uptake and ATP content were reduced in the phloridzin group compared with the control group (P<0.05); the decrease was more obvious in the combined treatment group, and significant differences were found between the combined treatment group and all other groups (P<0.05). The caspase-3 activity and apoptosis were increased in the sorafenib group and phloridzin group compared with the control group (P<0.05), which were more obvious in the combined treatment group, and significant differences were found between the combined treatment group and all other groups (P<0.05). Conclusions：There may be a synergistic effect of the phloridzin and sorafenib, which may be mediated by inhibiting the ATP generation and promoting the apoptosis of hepatocellular carcinoma cells.