Angiogenesis, the growth of new blood vessels, is a critical homeostatic mechanism which regulates vascular populations in response to physiologic requirements and pathophysiologic demand, including chronic inflammation and cancer. The importance of angiogenesis in gastrointestinal chronic inflammation and cancer has been defined, as anti-angiogenic therapy has demonstrated benefit in models of inflammatory bowel disease and colon cancer treatment. Curcumin is a natural product undergoing evaluation for the treatment of chronic inflammation, including inflammatory bowel disease (IBD). The effect of curcumin on human intestinal angiogenesis is not defined. We examined the anti-angiogenic effect of curcumin on in vitro angiogenesis using primary cultures of human intestinal microvascular endothelial cells (HIMEC), stimulated with VEGF. Curcumin inhibited proliferation, cell migration and tube formation in HIMEC induced by VEGF. Activation of HIMEC by VEGF resulted in enhanced expression of COX-2 mRNA, protein and PGE2 production. Pre-treatment of HIMEC with 10 uM curcumin as well as 1 uM NS398, a selective inhibitor of COX-2, resulted in inhibition of COX-2 at the mRNA and protein level and PGE2 production. Similarly COX-2 expression in HIMEC was significantly inhibited by JNK (SP600125) and p38 MAPK (SB203580) inhibitors and was reduced by p44/42 MAPK inhibitor (PD098059). Taken together these data demonstrate an important role for COX-2 in the regulation of angiogenesis in HIMEC via MAPKs. Moreover, curcumin inhibits microvascular endothelial cell angiogenesis through inhibition of COX-2 expression and PGE2 production, suggesting that this natural product possesses anti-angiogenic properties, which warrants further investigation as adjuvant treatment of IBD and cancer.