Objective— Peroxisome proliferator-activated receptor γ (PPARγ) is widely expressed in vessel walls, and it's activation by agonists showed beneficial effects in cardiovascular diseases. However, the role of endothelial cell (EC) PPARγ in atherogenesis is not fully understood. Methods and Results— To assess the contribution of endothelial-specific PPARγ in atherosclerosis, EC-specific PPARγ disruption and LDL receptor (LDLR) double-knockout (PPARγ ΔEC /LDLR −/− ) mice were developed. When challenged with a high-cholesterol diet for 4 weeks, PPARγ ΔEC /LDLR −/− mice exhibited severe atherosclerotic lesions compared to either their littermate controls or macrophage-specific PPARγ disruption and LDLR double knockout (PPARγ ΔMΦ /LDLR −/− ) mice. Metabolic analysis showed severe dyslipidemia and significant increase in systolic blood pressure in the PPARγ ΔEC /LDLR −/− mice. Histological analysis and real-time quantitative PCR suggested an exacerbated inflammation in PPARγ ΔEC /LDLR −/− mice, as revealed by the increases of proinflammatory gene expression and macrophage infiltration in vivo and in vitro. Furthermore, in vivo endothelial permeability was also increased by endothelial PPARγ disruption. Bone-marrow transplantation studies, which reconstituted hematopoietic PPARγ, demonstrated that the accelerated atherogenesis was due to endothelial PPARγ deficiency. Conclusion— Endothelial PPARγ plays an important protective role in atherogenesis.