More than one third of human soft tissue sarcoma (STS) have elevated levels of the MDM2 oncoprotein, resulting either from gene amplification or alternate mechanisms. MDM2 functions as a negative feedback regulator of the tumor suppressor p53. The aim of the present study was to investigate whether mdm2-antisense oligodeoxyribonucleotides (AS-ODNs) can influence the growth characteristics of two MDM2-overexpressing STS cell lines (US8-93, LMS6-93) where both have heterozygous p53 non-missense mutations. Cells were treated with lipofectamine-complexed mdm2 AS-ODNs complementary to a sequence of the mdm2 cDNA initiation site in comparison to sense control ODNs. After seeding and cultivation of a defined cell number the clonogenic survival was performed. The treatment of US8-93 cells with AS-ODNs, but not with sense ODNs, decreased the number of colonies up to > 80%. Western blot analysis demonstrated a significant decreasing of MDM2 protein level in AS-ODN transfected cells indicating an AS-specific inhibition of mdm2 transcription in US8-93 cells. Additionally, an increase of the G2/M population was found. In contrast, in the LMS6-93 cells treated with AS-ODNs only a decrease in clonogenic survival up to 26%, no change in MDM2 protein level and no cell cycle alterations were seen. All these factors taken together into consideration can be suggest that lipid-mediated mdm2 AS-ODNs could be as an effective therapeutic strategy for STS with an abnormal mdm2 overexpression.