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Background and Aims: Increased oxidative stress is associated with accelerated atherosclerosis. Emerging evidence highlights the role of heparanase in atherogenesis, where heparanase inhibitor PG545 reduces oxidative stress in apolipoprotein E deficient mice (E 0 mice). Herein, we studied the effects of PG545 on atherosclerosis progression in E 0 mice., Methods: Male E 0 mice fed a high-fat diet (n = 20) were divided into 3 groups treated with weekly intraperitoneal injections of either low (0.2 mg/mouse) or high dose (0.4 mg/mouse)PG545 or normal saline (controls) for twelve weeks. Body weight and food intake were measured weekly. At the end of the treatment period, blood pressure was measured, animals were sacrificed and serum samples were collected and assessed for biochemical parameters and oxidative stress. Aortic vessels and livers were collected for atherosclerotic plaques and histopathological analysis, respectively., Results: Blood pressure decreased in mice treated with low, but not high dose of PG545. In addition, heparanase inhibition caused a dose-dependent reduction in serum oxidative stress, total cholesterol, low-density lipoproteins, triglycerides, high-density lipoproteins, and aryl esterase activity. Although food intake was not reduced by PG545, body weight gain was significantly attenuated in PG545 treated groups. Both doses of PG545 caused a marked reduction in aortic wall thickness and atherosclerosis development, and liver steatosis. Liver enzymes and serum creatinine were not affected by PG545., Conclusions: Heparanase inhibition by PG545 caused a significant reduction in lipid profile and serum oxidative stress along with attenuation of atherosclerosis, aortic wall thickness, and liver steatosis. Moreover, PG545 attenuated weight gain without reducing food intake. Collectively, these findings suggest that heparanase blockade is highly effective in slowing atherosclerosis formation and progression, and decreasing liver steatosis., (Copyright © 2018 Elsevier B.V. All rights reserved.)