Recent studies have demonstrated the presence of unesterified cholesterol-rich, liposome-like vesicles in the extracellular space of atherosclerotic lesions in humans and animals. Liposome-like vesicles accumulate in the subendothelial space in rabbits within 2 weeks of initiation of cholesterol feeding, well before foam cells appear. These observations suggest that extracellular liposome-like vesicles may play a pivotal role in atherogenesis. The origin of these particles is unknown. We report a combination of in vivo and in vitro experiments that suggest a novel origin for these liposome-like vesicles. We demonstrate that the liposome-like particles isolated from postmortem human atherosclerotic plaques are rich in intact apolipoprotein (apo) A-I, C apolipoproteins, and sphingomyelin. We show that the in vivo derived particles are virtually identical, structurally and compositionally, to liposome-like lipolytic surface remnants of triglyceride (TG)-rich lipoproteins produced during in vitro lipolysis of hypertriglyceridemic serum. In vitro lipolysis of isolated very-low-density lipoprotein has shown that the lipolytic surface remnants remain attached to the core remnants in the absence of high-density lipoprotein (HDL), dissociate to form liposomelike vesicles in the presence of low levels of HDL, and are assimilated into HDL to form larger HDL particles in the presence of excess HDL. Thus, the in vitro produced, liposome-like particles represent a complex of lipolytic surface C holesterol deposition in the arterial intima is characteristic of human atherosclerotic plaques. 1 These deposits represent both intracellular lipid droplets (foam cells) and extracellular lipid particles. The cholesterol deposits in fibrous plaques are predominantly extracellular. 2Several recent studies have shown that atherosclerotic lesions in both humans and experimental animals contain numerous large, extracellular, liposome-like particles, which differ from extracellular spheroidal very-low-density lipoprotein (VLDL)-and low-density lipoprotein (LDL)-like particles and intracellular lipid droplets in foam cells with respect to size and chemical composition. 310 In animal models these particles accumulate before foam cells appear, emphasizing the primacy of these particles in atherogenesis.