We have previously reported that the introduction of macrophage apoE into mice lacking both apoE and the LDL receptor (apoE(-)(/-)/LDLR(-)(/-)) through bone marrow transplantation (apoE(+)(/+)/LDLR(-)(/-)-->apoE(-)(/-)/LDLR(-)(/-)) produces progressive accumulation of apoE in plasma without affecting lipid levels. This model provides a tool to study the effects of physiologically regulated amounts of macrophage apoE on atherogenesis in hyperlipidemic animals. Ten-week-old male apoE(-)(/-)/LDLR(-)(/-) mice were transplanted with either apoE(+)(/+)/LDLR(-)(/-) (n = 11) or apoE(-)(/-)/LDLR(-)(/-) (n = 14) marrow. Although there were no differences between the two groups in lipid levels at baseline or at 5 and 9 weeks after transplantation, apoE levels in the apoE(+)(/+)LDLR(-)(/-)-->apoE(-)(/-)/LDLR(-)(/-) mice increased to 4 times the apoE levels of normal mice. This resulted in a 60% decrease in aortic atherosclerosis in the apoE(+)(/+)/LDLR(-)(/-)-->apoE(-)(/-)/LDLR(-)(/-) compared with the apoE(-)(/-)/LDLR(-)(/-)-->apoE(-)(/-)/LDLR(-)(/-) controls, (15957 +/- 1907 vs. 40115 +/- 8302 micro m(2) +/- SEM, respectively). In a separate experiment, apoE(+)(/+)/LDLR(-)(/-) mice were transplanted with either apoE(+)(/+)/LDLR(-)(/-) or apoE(-)(/-)/LDLR(-)(/-) marrow and placed on a high-fat diet for 8 weeks. In the absence of macrophage apoE, lesion area was increased by 75% in the aortic sinus and by 56% in the distal aorta. These data show that physiologic levels of macrophage apoE in the vessel wall are anti-atherogenic in conditions of severe hyperlipidemia and can affect later stages of plaque development.