p53 replacement gene therapy has been carried out clinically for cancers with p53 mutations; however, some cancers are resistant to p53 gene therapy. In this study, we transduced A-172 and U251 cells harboring p53 mutations with wild-type p53 using adenovirus vectors to induce wild-type p53 protein at similar expression levels. A-172 cells did not undergo apoptosis after p53 transduction, whereas U251 cells were markedly sensitive to p53-mediated apoptosis, A-172 cells showed higher endogenous expression of Bcl-X-L than U251, and transduction of Bcl-X-L repressed p53-mediated apoptosis in U251 cells, suggesting that high endogenous expression of Bcl-X-L renders A-172 cells, at least in part, resistant to p53-mediated apoptosis. We transduced A-172 cells and U251 cells with the Apaf-1 or caspase-9 genes; both are downstream components of p52-mediated apoptosis, We found that A-172 cells were highly rrensitive to Apaf-1- and caspase-9-mediated apoptosis, The results indicate that A-172 cells harboring mutant p53 were not susceptible to p53-mediated apoptosis, possibly due to high endogenous expression of Bcl-X-L. Transduction of Apaf-1 or caspase-9 woulld override the resistance mechanism of apoptosis in A-172 cells. These findings provide potentially a novel approach in killing cancers that are resistant to p53 replacement gene therapy.