Abstract —The effect of monocyte/macrophage-derived wild-type mouse apolipoprotein E (apoE), human apoE3-Leiden, and human apoE2 on serum cholesterol levels and the development of atherosclerosis in apoE-deficient ( apoe–/– ) mice was investigated by using bone marrow transplantation (BMT). At 4 weeks after BMT, murine apoe+/+ bone marrow reduced serum cholesterol levels by 87% in apoe–/– mice, whereas macrophage-derived human apoE3-Leiden and human apoE2 induced a maximal, transient reduction of 35% and 48%, respectively. At 4 months after BMT, atherosclerosis was 23-fold ( P <0.001) reduced in apoe+/+ → apoe–/– mice, whereas no significant reduction in apoE3-Leiden. apoe–/– → apoe–/– and apoE2. apoe–/– → apoe–/– mice could be demonstrated. A highly significant decrease in serum cholesterol levels (78% reduction) and atherosclerosis (21-fold, P <0.001) was found in apoE3-Leiden. apoe–/– animals expressing high levels of apoE in multiple tissues, whereas apoE2 was ineffective even at high concentrations. Furthermore, in contrast to apoE-deficient macrophages, cholesterol efflux from apoE2 or apoE3-Leiden macrophages was not impaired. In conclusion, apoE3-Leiden as well as apoE2 are less effective in reducing cholesterol levels and atherosclerosis in apoe–/– animals, compared with apoe+/+, with apoE2<apoE3-Leiden< apoe+/+ , irrespective of the observed adequate efflux of cholesterol from macrophages expressing apoE2 and apoE3-Leiden, indicating that normalization of cholesterol efflux by macrophages is not accompanied by measurable effects on lesion growth.