OBJECTIVES: The aim of this study was to determine the relationship between atheroma regression and arterial wall remodeling. BACKGROUND: Infusion of reconstituted high-density lipoprotein (rHDL) containing recombinant apolipoprotein A-I Milano (AIM) has been reported to promote rapid regression of coronary atherosclerosis. The current study analyzed intravascular ultrasound (IVUS) to define the changes that take place in the arterial wall that accompanied atheroma regression in this study. METHODS: Forty-seven patients, ages 30 to 75 years, after an acute coronary syndrome were randomized to receive five weekly infusions of placebo or rHDL containing either low- or high-dose AIM. External elastic membrane (EEM) and lumen volumes were compared between coronary IVUS studies at baseline and follow-up. RESULTS: In comparison with baseline, infusion of rHDL was associated with a 4.6% reduction in EEM volume. Lumen volume did not change. In 10-mm arterial subsegments with the greatest plaque burden at baseline, atheroma volume regressed by 10.9% with a similar reduction in EEM volume but with no change in lumen size. In contrast, EEM and atheroma volume did not change in the 10-mm segments containing the least plaque burden. The reduction in EEM in the most diseased segments was only apparent in subjects who underwent plaque regression. Reduction in EEM volume correlated with the decreased atheroma volume (r = 0.62), but there was no correlation between change in lumen size and change in plaque volume. CONCLUSIONS: Remodeling of the arterial wall is a focal and heterogeneous process. After infusion of rHDL containing AIM, regression of coronary atherosclerosis is accompanied by reverse remodeling of the EEM, resulting in no change in luminal dimensions.