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, PGE₂ is 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 Apc^Δ716 mice (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 PGE₂ through the EP2 receptor via a positive feedback loop. Homozygous gene knockout for other PGE₂ receptors, EP1 or EP3, did not affect intestinal polyp formation in Apc^Δ716 mice. We conclude that EP2 is the major receptor mediating the PGE₂ signal 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.