Overexpression of Mdm2 in cancer cells with otherwise wild-type p53 is believed to be an alternative mechanism for p53 inactivation during carcinogenesis. Because a number of genetic alterations that inactivate p53, including mutation, homozygous deletion, or viral oncoprotein expression (e.g. HPV16-E6), inhibit DNA repair, we tested the hypothesis that Mdm2 would likewise inhibit DNA repair. Repair of cisplatin-induced DNA damage was reduced in MCF7 cells overexpressing Mdm2, compared to MCF7 cells in which wild-type p53 function was intact. MCF7-Mdm2 cells exhibited preferential sensitivity to cisplatin and carboplatin. MCF7-Mdm2 cells showed a pronounced S-phase arrest after cisplatin treatment, similar to that observed in mutant-p53 cells in the present and prior studies. MCF7 cells with intact wild-type p53, on the other hand, arrested primarily in G2/M phase after cisplatin treatment. These findings indicate that Mdm2 overexpression can recapitulate the effect of p53 mutations on DNA repair of cisplatin lesions.