Previous studies have demonstrated that macrophage-derived apolipoprotein E (apoE) reduces atherosclerotic lesion formation in lean apoE deficient (^-/-) mice. ApoE has also been demonstrated to play a role in adipocyte differentiation and lipid accumulation. Because the prevalence of obesity has grown to epidemic proportions we sought to determine whether macrophage-derived apoE could impact atherosclerotic lesion formation or adipose tissue expansion and inflammation in obese apoE^-/- mice. To this end, we transplanted obese leptin deficient (ob/ob) apoE^-/- mice with bone marrow from either ob/ob;apoE^-/- or ob/ob;apoE^+/+ donors. There were no differences in body weight, total body adipose tissue, or visceral fat pad mass between recipient groups. The presence of macrophage-apoE had no impact on adipose tissue macrophage content or inflammatory cytokine expression. Recipients of apoE^+/+ marrow demonstrated 3.7-fold plasma cholesterol (P<0.001) and 1.7-fold lower plasma triglyceride levels (P<0.01) by 12 weeks after transplantation. This was due to a dramatic decrease in VLDL and a mild increase in HDL levels. Atherosclerotic lesion area was over 10-fold lower in recipients of ob/ob;apoE^+/+ marrow (P<0.005). Similar results were seen in leptin receptor deficient (db/db) apoE^-/- mice. Finally, when bone marrow transplantation was performed in 4 month old ob/ob;apoE^-/- and db/db;apoE^-/- mice with pre-existing lesions, recipients of apoE^+/+ marrow had a 2.8-fold lower lesion area than controls (P=0.0002). These results demonstrate that macrophage-derived apoE does not impact adipose tissue expansion or inflammatory status; however, even very low levels of macrophage-derived apoE are capable of reducing plasma lipids and atherosclerotic lesion area in obese mice.