In the past few years, much effort has been devoted to show the single-target specificity of nongenotoxic, p53 reactivating compounds. However, the divergent biological responses induced by the different compounds, even in the same tumor cells, demand additional mechanistic insights, whose knowledge may lead to improved drug design or selection of the most potent drug combinations. To address the molecular mechanism underlying induction of mitotic arrest versus clinically more desirable apoptosis, we took advantage of two MDM2 antagonists, Nutlin-3 and RITA, which respectively produce these two outcomes. We show that, along with p53 reactivation, the proapoptotic p53-activator HIPK2 is degraded by MDM2 in Nutlin-3-treated cells, but activated by transiently reduced MDM2 levels in RITA-treated ones. Gain- and loss-of-function experiments revealed the functional significance of MDM2-mediated HIPK2 regulation in cell decision between mitotic arrest and apoptosis in both types of p53 reactivation. These data indicate that strategies of p53 reactivation by MDM2 inhibition should also take into consideration MDM2 targets other than p53, such as the apoptosis activator HIPK2.