OBJECTIVE: To investigate the possible molecular mechanism of total glycosides of Chishao(Radix Paeoniae Rubra)(TG-RPR) on proliferation and apoptosis of hepatocellular carcinoma cells.METHODS: The proliferation of TG-RPR on Hep G2 cells was detected using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay. The apoptosis of Hep G2 cells was measured by annexin V-FITC/double staining. The phosphatase and tensin homolog deleted on chromosome ten(PTEN)/phosphatidylinositol 3-kinase(PI3 K)/protein kinase B(Akt) signaling pathway was evaluated by Western Blot and reverse transcription-polymerase chain reaction(RT-PCR).RESULTS: TG-RPR can up-regulation the expression of pro-apoptotic factors such as PTEN and BCL2-Associated X(Bax), down-regulation the expression of anti-apoptotic factors including B-cell lymphoma-2(Bcl-2), PI3 K, and Akt.CONCLUSION: TG-RPR significantly inhibits the proliferation of Hep G2 cells in a dose-dependent manner and promotes apoptosis. These results demonstrated TG-RPR has significant inhibitory effect on Hep G2 cells. These results identify a critical role of TG-RPR in proliferation and apoptosis of Hep G2 cells via modulating PTEN/PI3 K/Akt signaling pathway. TG-RPR may offer a promise as a potential pharmaceutical therapy for hepatocellular carcinoma.