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 ^−/− ), leptin-deficient (ob/ob), double-mutant (LDLR ^−/− ;ob/ob), and C57BL6 mice were fed standard chow. Double-mutant mice had higher levels of non-HDL ( P <0.001) and HDL ( P <0.01) cholesterol and of triglycerides ( P <0.001). They also had higher oxidative stress, evidenced by higher titers of autoantibodies against malondialdehyde-modified LDL ( P <0.001). 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 ^−/− mice ( P <0.01). 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 ( P <0.01). The activity of the HDL-associated antioxidant enzymes paraoxonase and lecithin:cholesterol acyltransferase (LCAT) (ANOVA; P <0.0001 for both) was lower in double-mutant mice. Adenovirus-mediated LCAT gene transfer in double-mutant mice increased plasma LCAT activity by 64% ( P <0.01) and reduced the titer of autoantibodies by 40% ( P <0.01) and plaque volume in the aortic root by 42% ( P <0.05) 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.