ABSTRACT: Background: The effects of aggressive lipid-lowering therapy according to the number of diseased coronary arteries in acute coronary syndrome (ACS) are still controversial. This study investigated the efficacy of this therapy in ACS patients with multivessel disease (MVD) and single-vessel disease (SVD). Methods?and?Results: The subjects were derived from the HIJ-PROPER study, in which ACS patients with dyslipidemia were randomized to receive either pitavastatin+ezetimibe (targeting low-density lipoprotein cholesterol [LDL-C] <70 mg/dL) or pitavastatin monotherapy (targeting LDL-C <90 mg/dL). In this study, treatment efficacy was compared between patients with MVD and SVD. The primary endpoint was a composite of major advanced cardiovascular events (MACE; all-cause death, non-fatal myocardial infarction, non-fatal stroke, and ischemia-driven revascularization). We identified 1,702 eligible patients (MVD, n=869; SVD, n=833; mean age, 65.6 years; male, 75.6%; acute revascularization, 96.2%). MACE incidence was significantly higher in the MVD group than in the SVD group (43.7% vs. 25.9%, HR, 1.95; 95% CI: 1.65-2.31, P<0.001). In the SVD group, pitavastatin+ezetimibe had significantly fewer MACE than pitavastatin monotherapy (34.6% vs. 47.4%, HR, 0.72; 95% CI: 0.55-0.94, P=0.02). Conclusions: The benefits of aggressive lipid-lowering therapy, with the addition of ezetimibe to statins, were enhanced in ACS patients with SVD, but not with MVD, in the early invasive strategy era.