Herein, the major findings of the present study are: a) acquisition of p53 mutation contributed to the resistance of HCC cells to arsenic trioxide; b) activation of p73 by p53 knock down or Nutlin-3 could overcome arsenic trioxide resistance; c) Nutlin-3/arsenic trioxide combination could inhibit the tumor growth and metastasis of arsenic trioxide resistant HCC cells effectively through mutp53 degradation and activating p73 both in vivo and in vitro (Figure 6). This evidence concerns the gene TP53 and hepatocellular carcinoma.