We have reported recently that enrichment of high-density lipoprotein (HDL) with phosphatidylcholine (PC) liposomes is effective in solubilizing cholesterol from isolated human atherosclerotic plaques. In the present study, we investigated the in vivo effect of enrichment of HDL with PC on regression of diet-induced atherosclerosis in rabbits. As part of the study, a preliminary in vitro study on blood collected from the cholesterol-fed rabbits was performed to assess the capacity of the HDL density (d > 1.063 g/mL) plasma fraction from cholesterol-fed rabbits to assimilate multilamellar liposomes of synthetic dimyristoylphosphatidylcholine (DMPC). This was compared with the capacities of egg- and soy-PC liposomes to be assimilated into the HDL density plasma fraction. The capacity of the HDL density fraction to absorb PC from DMPC liposomes (11.5 mg/mL) was more than 10 times greater than egg or soy liposomes. Therefore, DMPC liposomes were chosen to infuse into cholesterol-fed rabbits. Cholesterol-fed rabbits infused weekly with DMPC liposomes (300 mg/kg body weight) for five weeks had significantly decreased aortic cholesterol contents (P < 0.05) compared with saline-infused cholesterol-fed controls. Atherosclerotic plaque volume, as measured by a type of new magnetic resonance imaging analysis, also decreased significantly (P < 0.05) after DMPC treatment. The present findings suggest that the enrichment of HDL with PC via intravenous infusion of synthetic DMPC liposomes could be a potential therapeutic approach for atherosclerotic plaque regression.