It is known from animal models that the cardioprotective nucleoside adenosine stimulates angiogenesis mainly through up-regulation of vascular endothelial growth factor (VEGF). Since macrophages infiltrate the heart after infarction and because adenosine receptors behave differently across species, we evaluated the effect of adenosine on VEGF in human macrophages. Adenosine dose-dependently up-regulated VEGF expression and secretion by macrophages from healthy volunteers. VEGF production was also increased by blockade of extracellular adenosine uptake with dipyridamole. This effect was exacerbated by the toll-like receptor-4 ligands heparan sulfate, hyaluronic acid and lipopolysaccharide, and was associated with an increase of hypoxia inducible factor-1alpha expression, the main transcriptional inducer of VEGF in hypoxic conditions. The agonist of the adenosine A2A receptor CGS21680 reproduced the increase of VEGF and the antagonist SCH58261 blunted it. In conclusion, these results provide evidence that activation of adenosine A2A receptor stimulates VEGF production in human macrophages. This study suggests that adenosine is a unique pro-angiogenic molecule that may be used to stimulate cardiac repair.