Lysophosphatidylcholine (lysoPC), a component of atherogenic lipoproteins and atherosclerotic lesions, has been recently suggested to play a role in atherogenesis. LysoPC is known to induce several endothelial genes involved in leukocyte recruitment, mitogenesis, and inflammation. Cyclooxygenases (prostaglandin H2 synthases) are rate-limiting enzymes involved in the endothelial synthesis of prostacyclin, an antiplatelet, vasorelaxant, and vasoprotective molecule. We investigated the effect of lysoPC on the endothelial expression of cyclooxygenases. Our results demonstrate that, in cultured human umbilical vein endothelial cells, lysoPC induces cyclooxygenase-2 mRNA and protein levels. Increased expression of cyclooxygenase-2 is accompanied by the enhancement of both basal- and calcium ionophore A23187-induced synthesis of prostacyclin. Nuclear runoff experiments demonstrated an increased rate of transcription of the cyclooxygenase-2 gene by lysoPC. In contrast, lysoPC did not affect the expression of constitutive cyclooxygenase-1. Our results suggest that the induction of endothelial cyclooxygenase-2 by lysoPC may be an important vasoprotective mechanism that limits progression of atherosclerotic lesions and promotes their regression.