Patients at risk of coronary heart disease may not achieve recommended low-density lipoprotein (LDL) cholesterol goals on statin monotherapy. This study was designed to investigate the efficacy and safety of rosuvastatin 40 mg alone or in combination with ezetimibe 10 mg in patients at high risk of coronary heart disease. Four hundred sixty-nine patients were randomly assigned to rosuvastatin alone or in combination with ezetimibe for 6 weeks. The primary end point was the percentage of patients achieving the Adult Treatment Panel III (ATP III) LDL cholesterol goal (<100 mg/dl) at week 6. Secondary end points included the percentage of patients achieving other ATP III and 2003 European lipid goals, changes from baseline in lipid, lipoprotein, and inflammatory parameters, and safety and tolerability. Significantly more patients receiving rosuvastatin/ezetimibe than rosuvastatin alone achieved their ATP III LDL cholesterol goal (<100 mg/dl, 94.0% vs 79.1%, p <0.001) and the optional LDL cholesterol goal (<70 mg/dl) for very high-risk patients (79.6% vs 35.0%, p <0.001). The combination of rosuvastatin/ezetimibe reduced LDL cholesterol significantly more than rosuvastatin (-69.8% vs -57.1%, p <0.001). Other components of the lipid/lipoprotein profile were also significantly (p <0.001) improved with rosuvastatin/ezetimibe. Both treatments generally were well tolerated. Rosuvastatin 40 mg was effective at improving the atherogenic lipid profile in this high-risk population. Combination rosuvastatin with ezetimibe 10 mg enabled greater decreases in LDL cholesterol and allowed more patients to achieve LDL cholesterol goals. In conclusion, rosuvastatin plus ezetimibe may improve the management of high-risk patients who cannot achieve goal on maximal statin monotherapy.