Low density lipoprotein (LDL) oxidation and monocyte infiltration of the vessel wall underlie atherogenesis. These cells express cyclooxygenase-2, but the way oxidized LDL stimulates cyclooxygenase-2 transcription is unknown. Oxidized LDL, oxidatively fragmented phospholipids isolated from oxidized LDL, a synthetic oxidized alkylphospholipid (azPC) that is a potent peroxisome proliferator activated receptor (PPAR) gamma agonist, or the PPARgamma agonist rosiglitazone all induced cyclooxygenase-2 expression and enhanced prostaglandin E(2) (PGE(2)) secretion in primary human monocytes. The cyclooxygenase-2 inhibitor NS398 blocked PPARgamma-induced PGE(2) secretion. Phospholipase A(1) and A(2) digestion shows that oxidized alkylphospholipids, and not oxidized fatty acids, were the relevant agonists. The upstream PPAR-responsive element (PPRE) of cyclooxygenase-2 was required for induction of a luciferase reporter by oxidized phospholipids, azPC, and rosiglitazone, and a (COX-2 PPRE)(3)-luciferase reporter was responsive to these PPARgamma agonists. Circulating human monocytes do not contain PPARgamma, but PPARgamma was induced rapidly (<4 h) in monocytes upon ligation of surface ICAM-3, but not P-selectin glycoprotein-1 even though both interactions prime cytokine secretion. Cyclooxygenase-2 induction by oxidized phospholipids only occurred in monocytes containing PPARgamma. Thus PPARgamma was induced rapidly in primary monocytes by appropriate outside-in signaling, sensitizing them to previously undetectable agonists in oxidized LDL. Cyclooxygenase-2 and PGE(2) secretion are induced, not inhibited, by selective PPARgamma agonists that include oxidatively fragmented phospholipids in oxidized LDL.