Background— The adipocyte fatty acid-binding protein (FABP) aP2 is expressed by adipocytes and macrophages and modulates insulin resistance, glucose and lipid metabolism, and atherosclerosis. Insulin sensitivity is improved in obese but not in lean aP2-deficient mice. A second fatty acid-binding protein, mal1, also is expressed in adipocytes and macrophages, and mal1 deficiency produces similar effects on insulin resistance. We tested the hypothesis that combined aP2 and mal1 deficiency would produce synergistic effects on metabolism and reduce atherosclerosis in apolipoprotein E-deficient (apoE −/− ) mice. Methods and Results— Male and female apoE −/− mice null for both aP2 and mal1 (3KO) and apoE −/− controls were fed a low-fat chow diet for 16 or 56 weeks. Lean 3KO mice had significantly lower serum cholesterol and triglycerides as well as improved insulin and glucose tolerance as compared with controls. Analysis of atherosclerotic lesions in the 3KO mice showed dramatic reductions in both early (20 weeks) and late-stage (60 weeks) atherosclerosis. Strikingly, survival in the 3KO mice was improved by 67% as compared with apoE −/− controls when challenged with the Western diet for 1 year. Conclusions— Combined aP2 and mal1 deficiency improved glucose and lipid metabolism, reduced atherosclerosis, and improved survival in apoE −/− mice, making these proteins important therapeutic targets for the prevention of the cardiovascular consequences of the metabolic syndrome.