To examine a possible synergistic role for p73 and cisplatin (cis-diamminedichloroplatinum II) in HeLa cells with a nonfunctional p53 protein, we established stable HeLa/p73 clones using a tetracycline inducible eukaryotic expression vector. The HeLa/p73 clones were not characterized by changes in growth or morphology. Cell death analysis, however, indicated a greater sensitivity to cisplatin in the p73-overexpressed HeLa cells than determined for the noninduced HeLa cells. This increased sensitivity seems to affect an induction of a sub-G1 population as assessed from flow cytometry analysis. The increased sub-G1 population may, in turn, result from a reduction of cyclin D1 and B1 expression by cisplatin in the presence of p73. Hoechest staining indicated an increased number of dead cells in the p73-induced cells compared to the non-induced cells. Poly ADP-ribose polymerase (PARP) cleavage was shown to be distinct in the p73-overexpressed cells compared to non-induced cells, which suggests that p73 modulates the cisplatin-induced apoptosis. Therefore, a synergistic effect of p73 and cisplatin to induce apoptosis could lead to new treatment for some types of human cancers.