The accumulation of lipids, especially cholesterol, in several vascular cell types such as macrophages and smooth muscle cells, is a defining pathologic feature of atherosclerosis. Serum amyloid A (SAA) isoforms 1.1 and 2.1 are acute phase proteins produced by the liver in response to any acute tissue injury. This chapter aims to characterize and define the effect of SAA2.1 on cholesterol efflux from cholesterol-laden macrophages in vivo. It demonstrates that the in vivo release of radiolabeled cholesterol from intravenously injected cholesterol-laden J774 macrophages is not a function of cell death nor of the destruction of these cells by an immune or ongoing inflammatory reaction but rather is dependent on a functional transporter. The cholesterol release was apparent within 6 h of the administration of isoform 2.1 or its relevant peptides, and peaked approximately16 h after the injection of these specific liposomes.