Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue tumors arising sporadically although more frequently in patients with Neurofibromatosis type 1. Prognosis remains dismal as chemo- and radiotherapy have not been shown to be successful. The heparin-binding growth factor, Midkine (MK), is implicated in the tumorigenesis of benign and plexiform neurofibromas, and thereof arising MPNSTs. MK is mitogenic, anti-apoptotic, angiogenic and can promote tumorigenicity in several cell types. Thus, we investigated the role of MK in malignant biology and tumorigenicity in MPNSTs by stable transfection into MPNST cell lines. Overexpression of MK in the MPNST cell line, S462, increased cell viability and protected cells from apoptosis under serum deprivation, but did not induce proliferation. In addition, MK-transfected S462 cells were partially protected from vincristine-induced cell death. Conditioned medium of MK-transfected S462 cells was a potent mitogen for human umbilical venous endothelial cells. Furthermore, MK overexpression in S462 cells was accompanied by higher levels of VEGF mRNA. Yet, stable overexpression of MK in S462 as well as in ST88-14 cells was not sufficient to promote xenograft tumor growth in nude mice. However, increasing survival and enhanced angiogenic potency of MK-transfected S462 cells highlight the importance of developing specific inhibitors for MK as part of new therapeutic concepts against MPNSTs.