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Background-Repeated doses of recombinant apolipoprotein A-I Milano phospholipid complex (apoA-I m ) reduce atherosclerosis and favorably change plaque composition in rabbits and mice. In this study, we tested whether a single high dose of recombinant apoA-I m could rapidly mobilize tissue cholesterol and reduce plaque lipid and macrophage content in apoE-deficient mice. Methods and Results-High cholesterol-fed, 26-week-old apoE-deficient mice received a single intravenous injection of saline (nϭ16), 1080 mg/kg dipalmitoylphosphatidylcholine (DPPC; nϭ14), or 400 mg/kg of recombinant apoA-I m complexed with DPPC (1:2.7 weight ratio; nϭ18). Blood was sampled before and 1 and 48 hours after injection, and aortic root plaques were evaluated for lipid content and macrophage content after oil-red O and immunostaining, respectively. One hour after injection, the plasma cholesterol efflux-promoting capacity was nearly 2-fold higher in recombinant apoA-I m -treated mice compared with saline and DPPC-treated mice (PϽ0.01). Compared with baseline values, serum free cholesterol, an index of tissue cholesterol mobilization, increased 1.6-fold by 1 hour after recombinant apoA-I m injection, and it remained significantly elevated at 48 hours (PϽ0.01). Mice receiving recombinant apoA-I m had 40% to 50% lower lipid content (PϽ0.01) and 29% to 36% lower macrophage content (PϽ0.05) in their plaques compared with the saline-and DPPC-treated mice, respectively. Conclusions-A single high dose of recombinant apoA-I m rapidly mobilizes tissue cholesterol and reduces plaque lipid and macrophage content in apoE-deficient mice. These findings suggest that this strategy could rapidly change plaque composition toward a more stable phenotype. (Circulation. 2001;103:3047-3050.)