Studies have shown a reduction in plaque volume and change in plaque ultrasound characteristics after 4 infusions of reconstituted high-density lipoprotein (rHDL). Whether rHDL infusion leads to acute changes in plaque characteristics in humans is not known. Patients with claudication scheduled for percutaneous superficial femoral artery revascularization were randomized to receive 1 intravenous infusion of either placebo or rHDL (80 mg/kg given over 4 hours). Five to 7 days following the infusion, patients returned and revascularization was performed including atherectomy to excise plaque from the superficial femoral artery. Twenty patients (17 males) average age, 68±10 years (mean±SD) were recruited. Eleven patients had a history of documented coronary artery disease, all patients were on aspirin, and 18 were on statins. Ten of the patients received rHDL and 10 placebo. There was significantly less vascular cell adhesion molecule-1 expression (28±3% versus 50±3%; P<0.05) and a reduction in lipid content in the plaque of HDL-treated subjects compared to placebo. The level of HDL cholesterol increased by 20% after infusion of rHDL and the capacity of apolipoprotein B–depleted plasma to support cholesterol efflux increased. Intravenous infusion of a single dose of reconstituted HDL led to acute changes in plaque characteristics with a reduction in lipid content, macrophage size, and measures of inflammation. These changes may contribute to the cardioprotective effects of HDL.