Soft tissue sarcomas (STSs) are a relatively rare tumour type, but they are characterized by high heterogeneity. It is difficult to predict the patients’ outcome and survival time. Therefore, STSs were comprehensively analysed according to the gene and expression status of various tumour suppressor and oncogenes, e.g. MDM2, TP53, p14ARF and others. We could show that alternatively as well as aberrantly spliced transcripts of the MDM2 mRNA were expressed in 55% of the tumour samples in addition to the full-length mRNA. In total, 20 different transcript variants have been identified. Of these, 16 have been described here for the first time. The expression of MDM2-splice variants is correlated to a more malignant phenotype in STS, but there was no impact on the patients’ overall survival time. We suggest that only certain isoforms contribute to tumorigenesis, whereas others do not. Unknown transcript variants have been characterized by a newly developed "Splice Capture Assay (SCA)". The SCA allows the rapid analysis of splice variants by simply comparing the restriction pattern obtained with selected restriction enzymes to that of known isoforms without sequencing. Of our STS samples, 28% contained an amplified MDM2 gene. Surprisingly, the MDM2 gene amplification was correlated to a prolonged survival time. Furthermore, a Cox-regression analysis revealed that the amplification of the MDM2 gene is an independent positive prognostic factor for STS (RR=4.4; p=0.17). The loss of ARF mRNA and protein expression was detected in 14% of the cases. This was significantly correlated to a shortened survival time for STS patients (11 vs. 96 months, p=0.0001, log-Rank-test). In summary, here we show that both the MDM2 gene amplification and the loss of p14ARF expression are independent prognostic markers for STS. Despite the contracting data regarding the prognostic value of MDM2 in STS, MDM2 has been considered as a target for a molecular therapeutic approach. We could show that the use of MDM2-antisense-oligonucleotides significantly reduces the tumour mass and the tumour number in an xenotransplant nu/nu-rat model compared to a sense-oligonucleotide and a saline control group. As expected, the amount of MDM2 protein was decreased in the tumours which have been treated with MDM2-antisense-oligonucleotides. Furthermore, we show for the first time, that the treatment with MDM2-antisense-oligonucleotides has an impact on the amount of mutant-TP53 which was significantly lower in the antisense-treated groups than in the control groups. These finding suggests that the MDM2-antisense-therapy acts independent from the TP53 mutational status, what might have an general impact on the treatment of cancer.