Vascular endothelial cell growth factor (VEGF) stimulates endothelial cell (EC) proliferation and migration and mediates vascular growth and angiogenesis through two receptors, VEGFR‐1 (Flt‐1) and VEGFR‐2 (KDR). Similar biological activity has been attributed to cyclooxygenase (COX)‐1 and ‐2, particularly in the angiogenic response to colon cancer. VEGF₁₆₅ (50 ng/ml for 3 h) increased the generation of 6‐keto‐PGF_1α in EC (2.8±0.36 ng/ml vs. 0.69±0.08 ng/ml, P < 0.05; n=9), which was prevented by the specific COX‐2 inhibitor NS398 (0.7±0.5 ng/ml). VEGF also induced COX‐2 protein expression. Extended exposure to VEGF (8–10 h) leads to COX‐1 protein expression. A peptide derived from the third globular domain of the VEGFR‐2 consisting of residues 247–261 (1 μM–1 mM) inhibited VEGF‐induced 6‐keto‐PGF_1α generation and COX induction. Prolonged exposure (7–9 h) of EC to VEGF induced cell proliferation that was inhibited by a combination of COX‐1 and ‐2 inhibitors (SC560 and NS398), suggesting that proliferation is dependent on both isoforms. The inhibitory effect of the combined inhibitors was also seen with aspirin and was reversed by the addition of the stable PGI₂ analog iloprost but not by the PGE₂ or PGH₂ analogs dinoprostone or U46619. In an angiogenic assay, new blood vessel formation induced by VEGF over 14 days was blocked by COX‐1 inhibition. COX induction and prostaglandin formation are downstream effectors of VEGF‐dependent EC activation and angiogenesis.