Arachidonic acid is metabolized to prostaglandin H2(PGH2) by cyclooxygenase (COX). COX-2, the inducible COX isozyme, has a key role in intestinal polyposis. Among the metabolites of PGH2, PGE2is implicated in tumorigenesis because its level is markedly elevated in tissues of intestinal adenoma and colon cancer. Here we show that homozygous deletion of the gene encoding a cell surface receptor of PGE2, EP2, causes decreases in number and size of intestinal polyps in ApcΔ716mice (a mouse model for human familial adenomatous polyposis). This effect is similar to that of COX-2 gene disruption. We also show that COX-2 expression is boosted by PGE2through the EP2 receptor via a positive feedback loop. Homozygous gene knockout for other PGE2receptors, EP1 or EP3, did not affect intestinal polyp formation in ApcΔ716mice. We conclude that EP2 is the major receptor mediating the PGE2signal generated by COX-2 upregulation in intestinal polyposis, and that increased cellular cAMP stimulates expression of more COX-2 and vascular endothelial growth factor in the polyp stroma.