Interactions of leukocytes with the vascular endothelium culminating in their diapedesis represent not only a crucial event in immune surveillance and defense, but are also critically involved in the pathogenesis of many inflammatory diseases including atherosclerosis. Our previous in vitro studies using atomic force microscopy measurement of monocyte-endothelial cell interaction have demonstrated that a cyclic arginine-glycine-aspartic acid peptide (cRGD) inhibited their adhesion through VLA4-VCAM-1 by 60% with the IC50=100 nM. To elucidate the potential efficacy of this peptide in vivo in preventing atherogenesis, experiments were performed in ApoE-/- mice fed a western diet and receiving chronic treatment with cRGD peptide for 2-4 weeks. In addition, some animals were subjected to a temporary carotid artery ligation while receiving the above treatment. Formation of fatty streaks and infiltration of the vascular wall with macrophages were not affected by cRGD treatment. Infiltration of the carotid artery post-ligation was significantly reduced in the cRGD-treated animals, as was the lipid accumulation. Furthermore, cRGDtreated ApoE-/- mice exhibited significantly lesser macrophage infiltration and lipid accumulation in the kidneys, the site of the highest expression of VLA4. These data demonstrated that cRGD peptide is a potent inhibitor of monocyte/macrophage infiltration of the injured macrovasculature and of the renal microvasculature, where it results in the attenuation of lipid accumulation. Formation of fatty streaks in the aortic root was not inhibitable by this treatment.