The progression of hepatocellular carcinoma (HCC) is known to be strongly related to overexpression of hepatitis Bx (HBx) protein and dysfunction of p53. While the inhibition of p53 by HBx is well known, the effect of p53 on HBx function has not been well studied. In this report, we found that p53 affects the stability of HBx protein. Overexpression of p53 protein reduced the level of HBx protein and downregulation of p53 protein by siRNA increased the level of HBx protein in HCC cell lines. This HBx degradation resulted in reduced HBx-mediated oncogenic signaling, such as activation of NF-kappaB and upregulation of cyclin D1. On the other hand, this p53-mediated HBx protein downregulation is impaired by the ablation of p53 nuclear function, which is accomplished by introducing a common feature of HCC, such as the mutation of p53 and endoplasmic reticulum (ER) stress. In addition, this ablation of p53 function increases HBx-mediated oncogenic signaling with a simultaneous increase in the HBx protein level. Our data suggest that p53 dysfunction in HCC can cause an upregulation of the HBx protein level through the stabilizing of HBx protein in HCC. This upregulation may induce the further progression of HCC.