Vascular endothelial growth factor (VEGF) has previously been shown to display neuroprotective effects following ischemia, suggesting that VEGF may potentially be applied as a neuroprotective agent for the treatment of other neurological diseases. In this study, we investigated the neuroprotective capacity of VEGF in a model of Parkinson's disease. VEGF was found to be neuroprotective against cell death of primary E14 murine ventral mesencephalic neurons induced by 6-hydroxydopamine (6-OHDA) treatment in vitro. Further, rats receiving a continuous infusion of VEGF into the striatum via encapsulated hVEGF-secreting cells (baby hamster kidney-VEGF) displayed a significant decrease in amphetamine-induced rotational behavior and a significant preservation of tyrosine hydroxylase-positive neurons and fibers compared with control animals. VEGF likely functions via direct mechanisms by signaling through the neuropilin receptor expressed upon dopaminergic neurons in response to 6-OHDA treatment. Further, VEGF is likely to promote neuroprotection indirectly by activating the proliferation of glia and by promoting angiogenesis. Our results support a potential neuroprotective role for VEGF in the treatment of Parkinson's disease.