The MDM2 oncogene plays an important role in tumorigenesis and especially in soft tissue sarcomas (STS). Overexpression of the MDM2 protein is associated with a poorer prognosis for STS patients. An MDM2 antisense approach to reduce MDM2 protein levels has been successfully applied on several carcinomas in vitro and used on a few in vivo cases. However, antisense treatment not only resulted in an MDM2 protein reduction but also in a wild-type P53 gene (wt-P53) mediated tumor growth suppression due to its genetic wt-P53 status. In this study, we used a clinically relevant xenotransplanted STS model with a mutated P53 gene (mt-P53) in order to exclude the influence of wt-P53. The human STSs were surgically implanted and one week later osmotic pumps were implanted intraperitoneally into nude rats releasing MDM2-antisense ODNs (AS ODNs) continuously for one week. As controls MDM2-sense ODN (SE ODN) or a 0.9% NaCl solution (saline solution) were administered. After one week animals treated with MDM2-AS ODN (100 or 200 microg) showed a reduction in tumor mass in comparison to animals treated with MDM2-SE ODN. The reduction in tumor mass was significant in animals treated with MDM2-AS ODNs in comparison to the saline solution treated ones (p=0.018 or p=0.007). Furthermore, a significant reduction in macroscopically visible tumor number with MDM2-AS ODN treatments (100 or 200 microg) in comparison to MDM2-SE ODN or saline solution treatment (both p=0.009) was observed for the first time. As expected a reduction in MDM2 protein expression in the MDM2-AS ODN treated tumors when compared to the MDM2-SE ODN or saline solution treated tumors was detected in Western blot analyses and immunohistochemically. In addition, an unexpected reduction in mt-P53 protein expression after AS ODN therapy was also observed. In short, we have demonstrated in vivo for the first time that MDM2-AS ODN treatment of xenotransplanted STS (mt-P53) reduces tumor mass, tumor number, MDM2 protein and mt-P53 protein expression. Our findings support the hypothesis that MDM2-AS ODN treatment may exert a tumor inhibiting effect on all MDM2 expressing tumors regardless of the P53-status, this in turn may be of general importance in gene therapy of cancer.