Two major markers for atherosclerosis are increased plasma cholesterol levels and low levels of high density lipoproteins (HDL). Human apolipoprotein (apo) A-I, the major protein component of HDL, has been shown to inhibit atherosclerosis in vivo without altering plasma cholesterol levels, perhaps through its antioxidant effect on low density lipoproteins (LDL). On the other hand, apo E inhibits atherosclerosis by enhancing the uptake of atherogenic lipoproteins by the liver and thus lowering plasma cholesterol levels. The class A amphipathic peptide 18A (DWLKAFYDKVAEKLKEAF) and its analogues, designed based on the lipid-associating amphipathic helical motif present in apo A-I, have been shown by us to mimic properties of apo A-I. Recently, we have shown that administration of an analogue of 18A was also able to inhibit atherosclerosis in atherosclerosis-sensitive mice, similar to apo A-I, without altering the plasma cholesterol levels. Based on the presence of two domains in apo E, the lipid-associating domain and the receptor-binding cationic domain, linking residues 141-150 of apo E to 18A resulted in a peptide that enhanced the uptake of atherogenic lipoproteins in vitro. Administration of this peptide into dyslipidemic mice showed a dramatic decrease in plasma cholesterol levels. These results demonstrate the potential for the design of peptides to ameliorate atherosclerosis, the number one cause of mortality in the developed countries.