Previously, we identified YueF as a novel Hepatitis B virus X protein (HBx)-interacting protein. Herein, we studied the functions of YueF and HBx in hepatocarcinogenesis. YueF was expressed at high levels in normal human hepatic cells and tissues, but scarcely found in hepatoma cells or other tumor tissues. Over-expression of YueF, or YueF and HBx could induce cell apoptosis and enhance p53 expression in hepatoma cells, whereas over-expression of HBx alone behaved contrarily. These results indicate that YueF has tumor suppressor activity and affects the functions of HBx in cell apoptosis and p53 expression in hepatoma cells.