Atherosclerosis is a complex disease initiated by the vascular accumulation of lipoproteins in the sub-endothelial space, followed by the infiltration of monocytes into the arterial intima. Caveolin-1 (Cav-1) plays an essential role in the regulation of cellular cholesterol metabolism and of various signaling pathways. In order to study specifically the role of macrophage Cav-1 in atherosclerosis, we used Cav-1−/−Apoe−/− mice and transplanted them with bone marrow (BM) cells obtained from Cav-1+/+Apoe−/− or Cav-1−/−Apoe−/− mice and vice versa. We found that Cav-1+/+ mice harboring Cav-1−/− BM-derived macrophages developed significantly larger lesions than Cav-1+/+ mice harboring Cav-1+/+ BM-derived macrophages. Cav-1−/− macrophages were more susceptible to apoptosis and more prone to induce inflammation. The present study provides clear evidence that the absence of Cav-1 in macrophage is pro-atherogenic, whereas its absence in endothelial cells protects against atherosclerotic lesion formation. These findings demonstrate the cell-specific role of Cav-1 during the development of this disease.