Objective: Caveolin-1 (Cav-1) may positively or negatively influence the development of atherosclerosis, depending on the cell type and the metabolic pathways regulated by this protein. We investigate the effects of Cav-1 on cholesterol efflux in RAW264.7 infected with AdPPARγ1 and whether Cav-1 could attenuate established atherosclerotic lesions in PPARγ1-treated apoE-deficient mice. Methods and Results: Compared with AdGFP control, PPARγ1 and Cav-1 were constitutively overexpressed in AdPPARγ1-infected RAW264.7 cells, which stimulated cholesterol efflux to apolipoprotein A-I. Using a small interfering RNA approach (Cav-1-siRNA) we achieved an efficient and specific knockdown of caveolin-1 expression (80%), which resulted in a remarkable reduction of cholesterol efflux in RAW264.7 cells . Moreover, PPARγ1-treated Cav-1-siRNA RAW264.7 cells showed more ability to stimulate cholesterol efflux than Cav-1-siRNA RAW264.7 cells, but far less than control-siRNA RAW264.7 cells and PPARγ1-treated RAW264.7 cells. In addition, 40-week-old apoE-deficient mice fed a Western-type diet and infected for 4 weeks with AdPPARγ1 showed induced Cav-1 expression in aortic vascular endothelial cells, smooth muscle cells and macrophages, as well as attenuated established atherosclerotic lesions. Conclusions: PPARγ1 gene therapy could induce Cav-1 expression and enhance cholesterol efflux and attenuate atherosclerosis in apoE-deficient mice.