AIM: To investigate the effect of CP466722, an inhibitor of ataxia telangiectasia mutated protein (ATM), on the proliferation and apoptosis of human hepatocellular carcinoma HepG2 cells.METHODS: The cell viability was detected by MTT assay.The cell growth inhibition was measured by colony formation assay.The effect of CP466722 on the cell cycle distribution of the HepG2 cells was examined by flow cytometry.The cell apoptosis was analyzed by TUNEL staining.The protein expression was examined by Western blotting.RESULTS: CP466722 inhibited the cell viability and cell proliferation in a dose-dependent manner.In CP466722-treated HepG2 cells, the cell cycle was arrested in G2/M phase, and the protein levels of phosphorylated cell division cycle protein 2 (p-Cdc2), cell division cycle protein 25C (Cdc25C) and phosphorylated Cdc25C (p-Cdc25C) were inhibited, whereas the protein expression of p27 was up-regulated.CP466722 triggered the apoptosis of HepG2 cells through cleavages of caspase-3 and poly (ADP-ribose) polymerase (PARP).In addition, CP466722 increased the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) and suppressed the expression of β-catenin and survivin in the HepG2 cells.CONCLUSION: CP466722 inhibits the proliferation and induces the apoptosis of HepG2 cells, which may be related to activating p38 MAPK and inhibiting the expression of β-catenin and survivin.