A modified p53 enhances apoptosis in sarcoma cell lines mediated by doxorubicin. Mdm2 is frequently overexpressed in sarcoma cells and may contribute to drug resistance by increasing p53 degradation. We investigated the induction of apoptosis in sarcoma cells via adenovirus-mediated gene transfer of wild-type p53 and two modified p53 genes, p53 14/19 and p53 22/23, whose protein products are resistant to Mdm2-mediated degradation. We found that adenovirus-wt p53 (Ad-wt p53) induces significant apoptosis in HT1080 fibrosarcoma cells expressing low levels of Mdm2, but fails to induce apoptosis in SJSA osteosarcoma cells expressing high levels of Mdm2. In contrast, Ad-p53 14/19 induces significant apoptosis in both cell lines. Interestingly, Ad-p53 22/23, a vector encoding a transcription-defective p53 mutant, causes limited apoptosis in both cell lines. We demonstrate that doxorubicin induces phosphorylation of both wt p53 and p53 14/19 protein at multiple sites. We tested the efficacy of doxorubicin and cisplatin with either Ad-wt p53, Ad-p53 22/23 or Ad-p53 14/19. SJSA cells, although harbouring endogenous wt p53, did not undergo significant apoptosis following doxorubicin or cisplatin exposure alone or combined with Ad-wt p53. In contrast, doxorubicin or cisplatin plus Ad-p53 14/19 induced significant apoptosis. Gene transfer of p53 14/19 in combination with the administration of doxorubicin or cisplatin is a potential therapeutic approach for cancers expressing high levels of Mdm2.