Cyclooxygenase-2 (COX-2), an inducible isoform protein, regulates diverse biological actions in vascular pathophysiology. COX-2 is induced in response to numerous stimuli, which results in prostaglandin (PG) production related to inflammation. Crotonaldehyde (CRA) is an extremely toxic α, β-unsaturated aldehyde and a major compound found in cigarette smoke. α, β-Unsaturated aldehyde in cigarette smoke is thought to mediate inflammation and vascular dysfunction. In this study, we evaluated the effect of CRA stimulation on COX-2 expression in human umbilical vein endothelial cells. CRA-stimulated COX-2 induction was accompanied by enhanced p38 phosphorylation and PGE2 generation. However, CRA-induced PGE2 production was reduced by pretreatment with an inhibitor of p38 MAPK. These results demonstrated that in human endothelial cells, CRA-induced COX-2-dependent PGE2 generation was mediated by p38 MAPK, and CRA may play a role in the development of inflammation.