Objective: We recently described anti-atherogenic properties of the dual domain peptide Ac-hE18A-NH2 derived by covalently linking the heparin binding domain 141-150 of apoE to 18A, a class A amphipathic helical peptide. In this paper we have compared the properties of Ac-hE18A-NH2 with the non-heparin binding 151-160 region of apoE linked to 18A (Ac-nhE18A-NH2). Methods and results: Both peptides were highly helical in solution and in association with lipids. Ac-hE18A-NH2 and not Ac-nhE18A-NH2 enhanced uptake of low density lipoprotein (LDL) in HepG2 cells. While Ac-hE18A-NH2 retarded the electrophoretic mobility of LDL, Ac-nhE18A-NH2 slightly enhanced mobility. Ac-hE18A-NH2 reduced monocyte association with endothelial cells, while Ac-nhE18A-NH2 increased it. Ac-hE18A-NH2 also reduced lipid hydroperoxide content of LDL while Ac-nhE18A-NH2 increased it. A single administration of Ac-hE18A-NH2 (100μg/mouse) into apoE null mice dramatically reduced cholesterol (from 600mg/dL to 180mg/dL at 5min and to 60mg/dL at 5h) while Ac-nhE18A-NH2 had no effect. Administration (100μg/mouse/day, three days a week) into apoE null mice for six weeks showed Ac-hE18A-NH2 group having a moderate aortic sinus lesion reduction compared with the control group (-15.1%), while the Ac-nhE18A-NH2 administered group had increased lesion area (+33.0% vs controls and 36.1% vs Ac-hE18A-NH2). Plasma from mice administered Ac-hE18A-NH2 for six weeks showed a significant reduction in plasma cholesterol and triglyceride levels and increase in paraoxonase-1 (PON-1) activity compared to controls, while Ac-nhE18A-NH2 caused no change in plasma cholesterol and decreased PON-1 activity. Conclusion: It is proposed that Ac-hE18A-NH2 reduced lesion progression in apoE null mice due to its anti-inflammatory and lipoprotein clearing properties, while Ac-nhE18A-NH2 exhibited pro-atherogenic effects. © 2010 Elsevier Ireland Ltd.