Monocyte-endothelial cell interactions have been implicated in the pathogenesis of a number of vascular diseases that target arterial and aortic endothelium, including atherosclerosis. Many different adhesion molecules, such as intercellular adhesion molecule (ICAM)-1, are thought to mediate monocyte binding to endothelial cells during the development of these diseases. However, conflicting results have been reported regarding the specific role of ICAM-1 in these events. In this study, we used a genetic approach to determine the contribution of ICAM-1 in mediating monocyte adhesion to mouse aortic endothelial cells (MAEC) derived from both wild-type and ICAM-1(-/-) mice. Treatment of wild-type MAEC with oxidized low-density lipoprotein significantly induced both WEHI 274.1 and whole blood monocyte adhesion, whereas similarly treated ICAM-1(-/-) MAEC showed a complete inhibition of monocyte binding. Dose-response treatment with tumor necrosis factor-alpha also increased monocyte adhesion to wild-type MAEC, but significant adhesion was only observed at higher doses for ICAM-1(-/-) MAEC. These data demonstrate a crucial role for ICAM-1-mediated monocyte-endothelial cell interactions in response to specific stimuli involved in inflammatory vascular diseases.