Background: Aliskiren is a direct renin inhibitor. It counteracts renin-angiotensin system and is used to treat hypertension. This study aims to evaluate the effect of aliskiren on the progression of atherosclerosis in domestic rabbits. Methods: Twenty-one local domestic rabbits were divided into three groups each group had special dietary regimen for 8 weeks: Group I (normal control), Group II (atherogenic control) and Group III (2% Cholesterol + aliskiren 40mg/kg/day orally). Blood samples were collected at the end of experiment (8 weeks) for measurement of serum lipid profile, plasma high sensitive C-reactive protein (hs-CRP), plasma malondialdehyde (MDA) and plasma reduced glutathione (GSH). Immunohistochemical analysis including vascular cell adhesion molecule-1 (VCAM-1); monocyte chemoattractant protein-1 (MCP-1); tumor necrotic factor -α (TNF-α); and interleukin -17 (IL-17). Histopathologic assessment of aortic atherosclerotic changes were also performed. Results: Compared to normal control group, there is a significant increase in the level of lipid profile, hs-CRP (134.1±1.2ug/L), and malondialdehyde (0.561±0.136umol/L) in the atherogenic diet group, while GSH was significantly reduced (0.58±0.024mmol/L) at (p ≤ 0.05). Immunohistochemical analysis showed that expression of aortic VCAM-1; MCP-1; TNF-α; and interleukin-17 were significantly increased in atherogenic control group compared to normal control group (p<0.001). In addition, animals on atherogenic diet have significant atherosclerotic lesion compared to normal control group. Aliskiren group appears to have no significant effect on lipid profile compared to atherogenic control group, but it has statistically significant reduction in hs-CRP (73.1±3.88ug/L) and MDA (0.261±0.15umol/L) at (p ≤ 0.05). Aliskiren treatment failed to significantly increase the level of plasma reduced glutathione. In addition, aliskiren treatment significantly reduced the expression of VCAM-1; MCP-1; TNF-α; and IL-17 (p≤0.05). Histopathological examination of aortic arch showed that aliskiren significantly reduced atherosclerotic lesion (p≤0.005). Conclusion: We can conclude that aliskiren is helpful in reducing lipid peroxidation, systemic inflammation and aortic expression of inflammatory markers used in this study and hence reduces the progression of atherosclerotic plague.