It has been shown that MDM2 inhibits the transcriptional and pro-apoptotic activities of p73 but does not promote its proteasomal degradation. In this study, we found that MDM2 indirectly induces the degradation of p73 through the interaction with Itch in HeLa cells. During adriamycin (ADR)-mediated apoptosis, p53 and p73 were induced to stabilize in association with a significant reduction of MDM2 and Itch, suggesting that, in addition to Itch, MDM2 could also be involved in the stability control of p73. As expected, forced expression of MDM2 resulted in a remarkable reduction of p73. MDM2-mediated degradation of p73 was inhibited by MG-132. Intriguingly, siRNA-mediated knockdown of Itch significantly attenuated the negative effect of MDM2 on p73. Additionally, MDM2 bound to Itch in HeLa cells but not in H1299 cells. Collectively, our present findings suggest that MDM2 promotes Itch-mediated degradation of p73 through the interaction with Itch in HeLa cells.