We previously reported that cyclooxygenase (COX)-2 was predominantly expressed in macrophages of human colonic adenomas (Int. J. Cancer 83, 470–475.). The role of prostaglandins (PGs) produced by COX-2-expressing macrophages in colon carcinogenesis is still unclear. Here we show that PGs up-regulate vascular endothelial growth factor (VEGF) production by activated macrophages through their specific receptors. mRNAs of both PGE-specific receptors and peroxisome proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily of ligand-dependent transcription factors, were expressed in phorbol 12-myristate 13-acetate-differentiated U937, a human macrophage model (H-Mac). Prostaglandin E₁ (PGE₁) and 15-deoxy-Δ^12,14-PGJ₂ (a potent PPARγ ligand, 15d-PGJ₂) dramatically increased VEGF production. The combination of PGE₁ and 15d-PGJ₂ additively increased VEGF production. In addition, PGE₁ significantly increased cAMP formation, whereas 15d-PGJ₂ did not affect cAMP formation. The effect of the combination of PGE₁ and 15d-PGJ₂ on cAMP formation was similar to that of PGE₁ alone. Unexpectedly, 15d-PGJ₂ also drastically increased IL-1β production, an indicator of macrophage activation, although PGE₁ only mildly increased it. Additional enhancement of IL-1β production was observed in the combination of PGE₁ and 15d-PGJ₂. These results suggest that PGs dramatically increased VEGF production by activated macrophages through specific PGE receptor and PPARγ-mediated processes and that PGs may thereby promote tumor growth through VEGF production.