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Abstract: Objective:: The purpose of this study was to evaluate the efficacy and safety profile of ezetimibe/simvastatin(EZE/SIMVA) combination tablet, relative to ezetimibe (EZE) and simvastatin (SIMVA) monotherapy, in patients with primary hypercholesterolemia. Methods:: This was a randomized, multicenter, double-blind, placebo-controlled, factorial design study Aftera 6- to 8-week washout period and 4-week, single-blind, placebo run in, hypercholesterolemic patients (low-density lipoprotein cholesterol [LDL-C], 145–250 mg/dL; triglycerides [TG], ≤350 mg/dL) were randomized equally to 1 of 10 daily treatments for 12 weeks: EZE/SIMVA 10/10, 10/20, 10/40, or 10/80 mg; SIMVA 10, 20, 40, or 80 mg; EZE 10 mg; or placebo. The primary efficacy analysis was mean percent change from baseline in LDL-C to study end point Secondary end points included percent changes in other lipid variables and C-reactive protein [CRP]. Results:: There were 1528 patients randomized to treatment (792 women, 736 men); mean (SD) age ranged from 54.9 (112) years to 56.4 (10.6) years across pooled treatment groups. The treatment groups were well balanced for baseline demographics. Pooled EZE/SIMVA was associated with greater reductions in LDL-C than pooled SIMVA or EZE alone (P < 0.001). Depending on dose, EZE/SIMVA was associated with reductions in LDL-C of −44.8% to −602%, non-high-density lipoprotein cholesterol of −40.5% to −55.7%, and TG of −22.5% to −30.7%; high-density lipoprotein cholesterol increased by 5.5% to 9.8%. EZE/SIMVA was associated with greater reductions in CRP and remnant-like particle-cholesterol than SIMVA alone (P < 0.001). More patients receiving EZE/SIMVA versus SIMVA achieved LDL-C concentrations <100 mg/dL (78.6% vs 45.9%; P < 0.001). EZE/SIMVA was generally well tolerated, with a safety profile similar to SIMVA monotherapy There were no significant differences between EZE/SIMVA and SIMVA in the incidence of consecutive liver transaminase levels ≥3 times the upper limit of normal (ULN) (1 .5% for EZE/SIMVA and 1.1% for SIMVA; P = NS) or creature kinase levels ≥10 times ULN (0.0% for EZE/SIMVA and 02% for SIMVA; P = NS). Conclusion:: The EZE/SIMVA tablet was a highlyeffective and well-tolerated LDL-C-lowering therapy in this study of patients with primary hypercholesterolemia. [Copyright &y& Elsevier]