Background: Atherosclerosis is a disease of large and medium-sized muscular arteries and is characterized by endothelial dysfunction, vascular inflammation, and the buildup of lipids, cholesterol, calcium, and cellular debris within the intima of the vessel wall, oxidized low-density lipoprotein (LDL) can reduce the expression of nitric oxide synthase, the enzyme that produces nitric oxide. Nitric oxide reduces injury to the vessel walls, which also helps prevent the development of atherosclerosis Recently, they discovered that pomegranate juice enhances the bioactivity of nitric oxide synthase in endothelial cells. Furthermore, pomegranate’s antioxidant properties protect nitric oxide from oxidative destruction, thus augmenting its biological actions. Therefore the objective of present study was to assess the effect of pomegranateon atherosclerosis regression via interfering with inflammatory and oxidative pathways. Methods: 60 local domestic rabbits were assigned to three groups: Group I (n = 30) fed normal diet,Group II ( n = 30) Rabbit fed high cholesterol-diet (induced untreated group), Group III ( n = 30) high cholesterol-diet for 12 weeks but adding oral pomegranate juice at 6 weeks .Blood samples were collected at (0 time ), after 6 and 12 weeks for measurement of serum triglycerides (TG), total cholesterol (TC), HDL-C and serum high sensitive C-Reactive Protein (hsCRP), serum IL-6 and serum TNF-a. At the end of 12 weeks,both carotid and right coronary arteries was removed, part of it for histopathology to assess the atherosclerotic change according to AmericanHeart Association classification of atherosclerosis phases and for aortic intema-media thickness also part of it homogenized for malondialdehyde (MDA) and reduced glutathione (GSH). Results: Compared with the control, levels of TC, TG, LDL-C, VLDL-C, atherogenic index, hsCRP, IL-6, TNF-a and arterial MDA were increased and arterial GSH and serum HDL-C were decreased in the animals with a high-choleterole diet ( P < 0.01). Histologically all induced-untreated rabbit showed significant atherosclerosis lesions in both arteries ( P < 0.01) all occurred at 6 and 12 weeks. While in pomegranate treated group at 12 weeks, levels of TC, TG, LDL-C, VLDL-C, atherogenic index, hsCRP, IL-6, TNF-a and arterial tissue of MDA were decreased and coronary and carotid GSH and serum HDL-C were increased relatively ( P < 0.01).Low power microscopic morphologic analysis revealed that pomegranate treated group markedly regressed ( P < 0.01) the atherosclerotic lesion in form of decrease intima-media thickness in histomorphometric measurements in the studied arteries at 12 weeks compared with rabbits on a high-fat diet at same period. In conclusion pomegranate juiceregressed atherosclerosis in carotid and coronary arteries in hypercholesterolemic rabbit via inhibition of inflammatory, oxidative pathways, reduced level of lipid parameters and decreased aortic intima-media thickness.