Versican/PG-M is an extracellular matrix proteoglycan, expression of which is elevated in a variety of human tumors. The significance of this change is unclear. Here we show that versican G3-containing fragments are present at high levels in human astrocytoma. Expression of a versican G3 construct in U87 astrocytoma cells enhances colony growth in soft agarose gel and tumor growth and blood vessel formation in nude mice. The G3-containing medium enhances endothelial cell adhesion, proliferation, and migration. G3-expressing cells and tumors formed by these cells express increased levels of fibronectin and vascular endothelial growth factor (VEGF). Furthermore, the G3 domain directly binds to fibronectin and forms a complex together with VEGF. In the presence of these three molecules, endothelial cell adhesion, proliferation, and migration were found to be significantly enhanced. Removal of the complex containing these molecules reverses these processes. Taken together, these findings implicate G3 as a modifier of tumor growth and angiogenesis and suggest a new avenue for development of anticancer and anti-angiogenic therapies based on targeting versican G3 fragments.