Aim To study hypolipidemic and anti-atherosclerosis effects and mechanisms of grape-seed polyphenols （GSP） in LDLR^-/- mice. Methods 7～8 weeks male LDLR^-/- mice （n32） were randomly divided into 4 groups with 8 mice in each group. One group was orally administrated with saline and fed with chow diet （normal control）. The other three groups were fed with a high fat diet containing 0.5% cholesterol and 20% lard and orally administrated with saline （hyperlipidemia control）, 5 mg/（kg·d） ezetimibe （positive drug control）, and 750 mg/（kg·d） GSP, respectively. Ezetimibe and GSP were dissolved in saline for administration. After a 12-week regimen, blood samples of the mice were collected by retro-orbital blood drawing for determining plasma TC and TG levels. All mice were then sacrificed and mouse aortas were isolated and dissected under microscope, and atherosclerotic lesions on aortic walls were stained by oil red O. Mouse aortic roots were frozenly sectioned for HE and oil red O staining, and Mac-2 immunohistochemistry staining as well. Besides, gene expression in mouse livers, related to lipid synthesis, oxidation, and metabolism, were measured by RT-PCR. Results Compared to saline treated hyperlipidemia control group, treating mice with GSP significantly decreased their TC and TG levels, significantly reduced atherosclerosis lesion area in mouse aortas and aortic roots, decreased macrophage infiltration in plaques, and up-regulated gene expression of LRP1 and CYP27A1 in mouse livers. Conclusions GSP has hypolipidemic effects and ameliorates atherosclerosis in LDLR^-/- mice. The hypolipidemic mechanisms of GSP may relate to regulation of alternative and neutral synthetic pathways of cholesterol metabolism, which results in an increase of cholesterol transference into bile acid, and improvement of lipid metabolism. The anti-atherosclerosis effects of GSP can be concluded to decrease of plasma TC and TG levels and reduction of foam cell formation.