By regulating the production of eicosanoids, cyclooxygenase (COX) modulates processes contributing to atherosclerosis and thrombosis, including platelet aggregation and the local inflammatory response. COX-2, a key mediator of inflammation, is upregulated in activated monocyte/macrophages, suggesting that COX-2 inhibition might reduce atherogenesis through its anti-inflammatory effects. In mouse models, selective inhibition of COX-2 or its deletion in macrophages protects against early atherosclerosis. The discovery that macrophage COX-2 is downregulated by oxidized low-density lipoprotein and liver X receptors indicates coordinated and reciprocal control of cholesterol homeostasis and inflammatory pathways. Thus, the impact of macrophage COX-2 expression on atherogenesis might be attenuated in advanced lesions. Concerns have been raised that inhibition of COX-2 might promote thrombotic cardiovascular events by disturbing the balance between platelet thromboxane A2 and endothelial prostacyclin. However, meta-analyses of randomized trials have failed to show excess of cardiovascular events among patients on COX-2 inhibitors. Prospective randomized evaluation of the effects of selective COX-2 inhibitors on cardiovascular events is warranted.