Angiopoietin-like protein family 4 (Angptl 4) has been shown to regulate lipoprotein metabolism through the inhibition of lipoprotein lipase (LPL). We generated ApoE −/−Angptl 4 −/− mice to study the effect of Angptl 4 deficiency on lipid metabolism and atherosclerosis. Fasting and postolive oil-loaded triglyceride (TG) levels were largely decreased in ApoE −/−Angptl 4 −/− mice compared with and ApoE −/−Angptl 4 +/+ mice. There was a significant (75 ± 12%) reduction in atherosclerotic lesion size in ApoE −/−Angptl 4 −/− mice compared with ApoE −/− Angptl 4 +/+ mice. Peritoneal macrophages, isolated from Angptl 4 −/− mice to investigate the foam cell formation, showed a significant decrease in newly synthesized cholesteryl ester (CE) accumulation induced by acetyl low-density lipoprotein (acLDL) compared with those from Angptl 4 +/+ mice. Thus, genetic knockout of Angptl 4 protects ApoE −/− mice against development and progression of atherosclerosis and strongly suppresses the ability of the macrophages to become foam cells in vitro.