Abstract Background Receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) is a chondroitin sulphate (CS) transmembrane protein tyrosine phosphatase and is a receptor for pleiotrophin (PTN). RPTPβ/ζ interacts with α ν β 3 on the cell surface and upon binding of PTN leads to c-Src dephosphorylation at Tyr530, β 3 Tyr773 phosphorylation, cell surface nucleolin (NCL) localization and stimulation of cell migration. c-Src-mediated β 3 Tyr773 phosphorylation is also observed after vascular endothelial growth factor 165 (VEGF 165 ) stimulation of endothelial cells and is essential for VEGF receptor type 2 (VEGFR2) - α ν β 3 integrin association and subsequent signaling. In the present work, we studied whether RPTPβ/ζ mediates angiogenic actions of VEGF. Methods Human umbilical vein endothelial, human glioma U87MG and stably transfected Chinese hamster ovary cells expressing different β 3 subunits were used. Protein-protein interactions were studied by a combination of immunoprecipitation/Western blot, immunofluorescence and proximity ligation assays, properly quantified as needed. RPTPβ/ζ expression was down-regulated using small interference RNA technology. Migration assays were performed in 24-well microchemotaxis chambers, using uncoated polycarbonate membranes with 8 μm pores. Results RPTPβ/ζ mediates VEGF 165 -induced c-Src-dependent β 3 Tyr773 phosphorylation, which is required for VEGFR2-α ν β 3 interaction and the downstream activation of phosphatidylinositol 3-kinase (PI3K) and cell surface NCL localization. RPTPβ/ζ directly interacts with VEGF 165 , and this interaction is not affected by bevacizumab, while it is interrupted by both CS-E and PTN. Down-regulation of RPTPβ/ζ by siRNA or administration of exogenous CS-E abolishes VEGF 165 -induced endothelial cell migration, while PTN inhibits the migratory effect of VEGF 165 to the levels of its own effect. Conclusions These data identify RPTPβ/ζ as a cell membrane binding partner for VEGF that regulates angiogenic functions of endothelial cells and suggest that it warrants further validation as a potential target for .