Background-Obesity-associated dyslipidemia in humans is associated with increased low-density lipoprotein (LDL) oxidation. Mice with combined leptin and LDL receptor deficiency are obese and show severe dyslipidemia and insulin resistance. We investigated the association between oxidation of apolipoprotein B-containing lipoproteins, high-density lipoprotein (HDL) antioxidant defense, and atherosclerosis in these mice. Methods and Results-LDL receptor knockout (LDLR Ϫ/Ϫ ), leptin-deficient (ob/ob), double-mutant (LDLR Ϫ/Ϫ ;ob/ob), and C57BL6 mice were fed standard chow. Double-mutant mice had higher levels of non-HDL (PϽ0.001) and HDL (PϽ0.01) cholesterol and of triglycerides (PϽ0.001). They also had higher oxidative stress, evidenced by higher titers of autoantibodies against malondialdehyde-modified LDL (PϽ0.001). C57BL6 and ob/ob mice had no detectable lesions. Lesions covered 20% of total area of the thoracic abdominal aorta in double-mutant mice compared with 3.5% in LDLR Ϫ/Ϫ mice (PϽ0.01). Higher macrophage homing and accumulation of oxidized apolipoprotein B-100 -containing lipoproteins were associated with larger plaque volumes in the aortic root of double-mutant mice (PϽ0.01). The activity of the HDL-associated antioxidant enzymes paraoxonase and lecithin:cholesterol acyltransferase (LCAT) (ANOVA; PϽ0.0001 for both) was lower in double-mutant mice. Adenovirus-mediated LCAT gene transfer in double-mutant mice increased plasma LCAT activity by 64% (PϽ0.01) and reduced the titer of autoantibodies by 40% (PϽ0.01) and plaque volume in the aortic root by 42% (PϽ0.05) at 6 weeks. Conclusions-Dyslipidemia and insulin resistance in obese LDL receptor-deficient mice are associated with increased oxidative stress and impaired HDL-associated antioxidant defense, evidenced by decreased paraoxonase and LCAT activity. Transient LCAT overexpression was associated with a reduction of oxidative stress and atherosclerosis.