The aim of this study was to determine the amplification status of the HDMX gene and the expression of the HDMX mRNA particularly that of the HDMX-S splice variant in soft tissue sarcomas (STS). We show that the HDMX gene is amplified in 27% of STSs, which was associated with a worse prognosis (RR = 2.8, p = 0.03). We have also found that the transcript of the HDMX-S variant was predominant in a subset of (14%) of tumor samples, which was correlated with a significantly decreased overall survival time (15 vs. 53 months, p < 0.0001, log-Rank-test) and with a 9-fold-increased risk of tumor-related death (p < 0.0001). There was no correlation between the HMDX gene amplification and the HDMX-S splice variant overexpression. In summary, our data indicate that both the overexpression of the HDMX-S transcript, as well as, the HDMX gene amplification are important prognostic markers for STS.