Adipose tissue secrets adipokines and fatty acids, which may contribute to obesity-associated vascular dysfunction and cardiovascular risk. This study investigated which factors are responsible for the synergistic effect of adipokine and oleic acid- (OA-) induced proliferation of human vascular smooth muscle cells (VSMC). Adipocyte-conditioned medium (CM) from human adipocytes induces proliferation of VSMC in correlation to its vascular endothelial growth factor (VEGF) content. CM increases VEGF-receptor (VEGF-R) 1 and 2 expression and VEGF secretion of VSMC, while OA only stimulates VEGF secretion. VEGF neutralization abrogates CM- and OA-induced proliferation and considerably reduces proliferation induced by CM and OA in combination. VEGF release is higher from visceral adipose tissue (VAT) of obese subjects compared to subcutaneous adipose tissue (SAT) and VAT from lean controls. Furthermore, VEGF release from VAT correlates with its proliferative effect. Perivascular adipose tissue (PAT) from type 2 diabetic patients releases significantly higher amounts of VEGF and induces stronger proliferation of VSMC as compared to SAT and SAT/PAT of nondiabetics. In conclusion, VEGF is mediating CM-induced proliferation of VSMC. As this adipokine is released in high amounts from VAT of obese patients and PAT of diabetic patients, VEGF might link adipose tissue inflammation to increased VSMC proliferation.