Background: The renin-angiotensin system (RAS) plays an important role in atherosclerosis. Acting via the angiotensin II receptor, type 1, oxidative stress increases and contributes to endothelial dysfunction and vascular inflammation. Renin exerts effects through a renin receptor causing an increase in the efficiency of angiotensinogen cleavage and facilitates angiotensin II (Ang II) generation and action on cell surfaces. Ang II enhances proliferation and migration of vascular smooth muscle cells, indicating a direct involvement of the RAS in smooth muscle cell proliferation during neointimal formation. Aliskiren, a direct renin inhibitor, is a new oral antihypertensive drug. However, the role of the direct renin inhibitor in neointimal formation and vascular matrix metalloproteinases remains unclear. Methods: To investigate the effects of aliskiren on the expression of vascular matrix metalloproteinases, we evaluated the aortic neointimal formation of high-cholesterol-fed animals after vascular injury in vivo and the cellular function of the tumor necrosis factor- stimulated human aortic smooth muscle cells in vitro. Thereafter, we evaluated vascular expression (by western blot), activity (by gelatin zymography) and molecular pathway. Results: In this study we demonstrated that aliskiren reduced neointimal hyperplasia in hypercholesterolemic rabbits after vascular injury and the expression of matrix metalloproteinases in the neointima. Aliskiren also inhibited the expression and activities ofmatrixmetalloproteinases on tumor necrosis factor- (TNF-)-stimulated human aortic smooth muscle cells via the mitogen-activated protein kinase pathway. Conclusions: The present study showed that aliskiren inhibited the expression of vascular matrix metalloproteinases. With these results, we have better clarified the potential role of renin inhibitors in human atherosclerosis.