Recent evidence indicates that renin-angiotensin system (RAS) plays an important role in the pathogenesis of atherosclerosis. It was reported that inhibition of RAS with angiotensin II type 1 receptor blockers (ARBs) or angiotensin converting enzyme inhibitors (ACEIs) is effective in prevention of atherosclerosis. Here, we investigated the effects of an ARB or/and an ACEI on atherosclerosis development and periadventitial inflammation in apolipoprotein E (ApoE)-deficient mice. RT-PCR revealed that major RAS components were expressed in periaortic tissue. Ang II infusion significantly increased accumulation of bone marrow derived cells into both neointima (p<0.05) and periaortic tissue (p<0.01). Male ApoE- deficient mice were treated with either vehicle, TA606A (10mg/kg/day, ARB), imidapril (3mg/kg/day, ACEI) or TA606A plus imidapril (TA606A 10mg/kg/day+imidapril 3mg/kg/day, ARB+ACEI) for 24 weeks starting at 12 weeks of age. ARB, ACEI, and ARB+ACEI significantly reduced atherosclerotic lesion formation in aorta compared with vehicle (p<0.05), with reduced expression of monocyte chemoattractant protein-1 in periaortic tissues (p<0.01). Neither blood pressure nor heart rate was changed by the treatments at these lower doses. Imidapril significantly reduced lipid deposition in atheroma and plasminogen activator inhibitor-1 expression in periadventitial tissue (p<0.05, respectively). Imidapril and combination therapy significantly attenuated macrophage infiltration into the atherosclerotic plaque (p<0.05, respectively). All treatments reduced macrophage accumulation in the periadventitial tissue 12 weeks after treatment (p<0.05, respectively). These results suggest that inhibition of renin-angiotensin system attenuates periadventitial inflammation and reduces atherosclerotic lesion formation.