Background: The enzyme acyl-coenzyme A:cholesterol acyltransferase (ACAT) esterifies cholesterol in a variety of tissues. In some animal models, ACAT inhibitors have antiatherosclerotic effects. Methods: We performed intravascular ultrasonography in 408 patients with angiographically documented coronary disease. All patients received usual care for secondary prevention, including statins, if indicated. Patients were randomly assigned to receive the ACAT inhibitor pactimibe (100 mg per day) or matching placebo. Ultrasonography was repeated after 18 months to measure the progression of atherosclerosis. Results: The primary efficacy variable analyzing the progression of atherosclerosis - the change in percent atheroma volume - was similar in the pactimibe and placebo groups (0.69 percent and 0.59 percent, respectively; P=0.77). However, both secondary efficacy variables assessed by means of intravascular ultrasonography showed unfavorable effects of pactimibe treatment. As compared with baseline values, the normalized total atheroma volume showed significant regression in the placebo group (-5.6 mm 3, P=0.001) but not in the pactimibe group (-1.3 mm 3, P=0.39; P=0.03 for the comparison between groups). The atheroma volume in the most diseased 10-mm subsegment regressed by 3.2 mm 3 in the placebo group, as compared with a decrease of 1.3 mm 3 in the pactimibe group (P=0.01). The combined incidence of adverse cardiovascular outcomes was similar in the two groups (P=0.53). Conclusions: For patients with coronary disease, treatment with an ACAT inhibitor did not improve the primary efficacy variable (percent atheroma volume) and adversely affected two major secondary efficacy measures assessed by intravascular ultrasonography. ACAT inhibition is not an effective strategy for limiting atherosclerosis and may promote atherogenesis. (ClinicalTrials.gov number, NCT00268515).