Heparin-binding EGF-like growth factor (HB-EGF), a member of the family of epidermal growth factors (EGFs), is involved in several biological processes and tumor formation. Several lines of evidence show that HB-EGF plays a key role in the acquisition of malignant phenotype. Studies show that HB-EGF expression is essential in oncogenesis of cancer-derived cell lines. HB-EGF is a promising target for cancer therapy. The aim of this study was to find new insights on the biological features of the soft tissue sarcomas, in order to consider the possibility to use HB-EGF as an immuno-target in histotype characterization and to facilitate therapeutic intervention. In our study we did HB-EGF-immunostaining on tissue samples collected from 43 human soft tissue sarcomas. We analyzed HB-EGF immunoexpression in some types of tumors such as clear cell sarcomas, leiomyosarcomas, phyllodes sarcomas, chondrosarcomas and liposarcomas. In relation to the different histotypes, we detected different immunostaining localization. From our results it was evident that pleomorphic cells, a signal of tumor progression, were HB-EGF immunostained, and this was accompanied by an extracellular matrix immunostaining. Moreover statistical analysis showed a correlation between HB-EGF immunostaining and the different types of analyzed soft tissue sarcomas. In conclusion, in some types of soft tissue sarcoma HB-EGF could be considered a useful diagnostic marker for their characterization.