Atherosclerotic　cardiovascular　disease　resulting　from　dysregulated　lipid　metabolism　is　the　leading　cause　of　morbidity　and　mortality　worldwide.　Apolipoprotein　E　(ApoE)　plays　a　critical　role　in　cholesterol　metabolism.　Knockouts　in　lipid-metabolizing　proteins　including　ApoE　in　multiple　model　organisms　such　as　mice　and　rats　exhibiting　elevated　levels　of　cholesterol　have　been　widely　used　for　dissecting　the　pathology　of　atherosclerosis,　but　few　of　these　animal　models　exhibit　advanced　atherosclerotic　plaques　leading　to　ischemia-induced　clinical　symptoms,　limiting　their　use　for　translational　studies.　Here　we　report　hypercholesterolemia　and　severe　atherosclerosis　characterized　by　stenosis　and　occlusion　of　arteries,　together　with　clinical　manifestations　of　stroke　and　gangrene,　in　ApoE　knockout　dogs　generated　by　CRISPR/Cas9　and　cloned　by　somatic　cell　nuclear　transfer　technologies.　Importantly,　the　hypercholesterolemia　and　atherosclerotic　complications　in　F0　mutants　are　recapitulated　in　their　offspring.　As　the　ApoE-associated　atherosclerosis　and　clinical　manifestations　in　mutant　dogs　are　more　similar　to　that　in　human　patients　compared　with　those　in　other　animal　models,　these　mutant　dogs　will　be　invaluable　in　developing　and　evaluating　new　therapies,　including　endovascular　procedures,　against　atherosclerosis　and　related　disorders.