Leptin is an adipocyte-derived hormone that has been shown to exert both beneficial metabolic effects and potentially adverse vascular effects in preclinical studies. The primary aim of this study was to determine the effects of leptin receptor signaling pathways on atherosclerosis in the setting of obesity and hyperlipidemia.Mice were generated with deficiency of apolipoprotein E (ApoE −/− ) and either wild-type leptin receptor expression (Lepr +/+ , ApoE −/− ), mutant leptin receptor expression defective in all leptin receptor signaling pathways (Lepr db/db , ApoE −/− ), or mutant leptin receptor expression with selective deficiency of leptin receptor-STAT3 signaling (Lepr s/s , ApoE −/− ). At 27 weeks of age (including 7 weeks on a Western diet), Lepr db/db , ApoE −/− developed severe obesity, hypercholesterolemia, and increased atherosclerosis compared to Lepr +/+ , ApoE −/− mice. Despite similar obesity and hyperlipidemia to Lepr db/db , ApoE −/− mice, Lepr s/s , ApoE −/− developed less atherosclerosis than Lepr db/db , ApoE −/− mice. Adipose tissue macrophage content, monocyte chemoattractant protein-1 and fatty-acid-binding protein 4 levels were also reduced in Lepr s/s , ApoE −/− mice compared to Lepr db/db , ApoE −/− mice.In a mouse model of obesity and hyperlipidemia, leptin receptor-mediated STAT3-independent signaling pathways confer protection against atherosclerosis. These differences occur independently of leptin effects on energy balance.