Abstract Objective To investigate the roles of glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) in the pathogenesis of hepatocellular carcinoma (HCC). Methods The expression of the GPI-PLD in HCC was determined. The GPI-PLD gene was stably transfected in HepG2 cells and the proliferation of these cells was detected; CD55, CD59 and apoptotic cells were also analyzed. Results The serum GPI-PLD activities, the protein and mRNA levels of GPI-PLD in HCC patients were decreased by 40%, 60% and 56%, respectively. The killing rate of CDC against the positive clone cells was significantly increased, but the proliferative capacity was obviously decreased. The apoptotic rate in positive clones was increased. Conclusion The expression of GPI-PLD decreases in HCC patients. The over-expression of GPI-PLD in HepG2 cells increases their sensitivity to CDC killing, impairs proliferative capacity and promotes apoptosis.