Objective: Aliskiren is the first commercially available, orally active, direct renin inhibitor approved to treat hypertension. The renin-angiotensin system has been shown to be a significant contributor to the development of hypercholesterolemia-induced atherosclerosis. The aim of this study was to evaluate the antiatherosclerotic and plaque stabilization effects of aliskiren alone and in combination with atorvastatin. Methods: APOE*3Leiden.CETP mice (n = 14-17/group) were fed a western-type diet (containing 0.25% cholesterol) alone or were treated with either aliskiren (15 mg/kg per day), atorvastatin (3.6 mg/kg per day) or a combination of aliskiren and atorvastatin. Effects on SBP, total cholesterol, inflammation markers and atherosclerotic size and composition were assessed. Results: Aliskiren reduced SBP (-19%, P < 0.001) and atorvastatin reduced total cholesterol (-24%, P < 0.001). Atherosclerotic lesion area was reduced by aliskiren (-40%, P < 0.01), atorvastatin (-61%, P < 0.001) and the combination treatment (-69%, P < 0.001). Aliskiren alone and together with atorvastatin decreased the number of T cells in the aortic root area (-60%, P < 0.01;-41%, P < 0.05), as well as macrophage (-64%, P < 0.001;-72%, P < 0.001) and necrotic area (-52%, P = 0.071;-84%, P < 0.001) in the lesion. Atorvastatin alone and together with aliskiren decreased monocyte adherence (-43%, P < 0.05 and-51%, P < 0.01) and monocyte chemoattractant protein-1 (both-36%, P < 0.01). The combination treatment decreased the number of lesions (-17%, P < 0.05) and E-selectin (-17%, P < 0.05). Conclusion: Aliskiren inhibited atherosclerosis development and improved plaque stability alone and in combination with atorvastatin, possibly via a mechanism involving T cells. These results suggest a potential benefit of using aliskiren in a clinical setting, particularly in combination with statin treatment. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.