Objective: The inhibition of cholesterol absorption by ezetimibe increases cholesterol synthesis. The effect of inhibition of cholesterol synthesis on cholesterol absorption is controversial. The influence of these interactions on cholesterol levels is unknown. We investigated the extent to which cholesterol levels were affected by the reaction of one pathway to the inhibition of the other pathway. Method: This case-controlled study enrolled 198 patients who needed cholesterol-lowering drugs based on the Adult Treatment Panel III guidelines. Ezetimibe (10 mg) was administered to patients with (n=58) and without on-going statin therapy (n=58). Simvastatin (20 mg) was administered to patients treated with (n=41) and without ezetimibe (n=41). Blood cholesterol levels were measured before and after 2 months of medications. Results: Ezetimibe without statin lowered cholesterol by 13.3짹8.8% (p=0.000) and low density lipoprotein-cholesterol (LDL-C) by 18.7짹15.3% (p=0.000). Ezetimibe added to statin decreased cholesterol by 21.1짹7.7% (p=0.000) and LDL-C by 29.9짹12.6% (p=0.000). Cholesterol and LDL-C were reduced more in patients with statin therapy than in those without statin therapy (p=0.000 and p=0.000, respectively). Simvastatin without ezetimibe lowered cholesterol by 28.9짹8.7% (p=0.000) and LDL-C by 41.1짹12.3% (p=0.000). Statin added to ezetimibe decreased cholesterol by 32.6짹7.8% (p=0.000) and LDL-C by 46.1짹11.3% (p=0.000). These differences were of borderline significance (p=0.10 and p=0.055, respectively). Conclusions: A prior inhibition of cholesterol synthesis by statin enhanced the effect of ezetimibe on cholesterol and LDL-C by 7.8% and 11.2%, respectively. This finding suggests that increased cholesterol synthesis due to the inhibition of cholesterol absorption results in significant elevation of cholesterol levels.