Background: Patients at high risk of cardiovascular disease frequently fail to reach recommended low-density lipoprotein cholesterol (LDL-C) goals, partly because statin doses are not titrated to optimal effect. The ECLIPSE study was designed to compare the efficacy and safety of force-titrated treatment with rosuvastatin (10–40 mg) with that of atorvastatin (10–80 mg) in high-risk patients with hypercholesterolemia. Methods: In this 24-week, open-label, randomized, multinational, parallel-group study, 1,036 patients were randomized to rosuvastatin (n = 522) or atorvastatin (n = 514). Results: At all time points, a significantly greater percentage of patients on rosuvastatin treatment achieved the NCEP ATP III LDL-C goal of <100 mg/dl (2.5 mmol/l), the 2003 European LDL-C target of <2.5 or 3.0 mmol/l (100 or 115 mg/dl) and the LDL-C goal of <70 mg/dl (1.8 mmol/l), a goal suggested for very high-risk patients (p < 0.001 for all). Rosuvastatin also achieved significantly greater improvements in components of the atherogenic lipid profile versus atorvastatin. Both treatments were well tolerated. Conclusion: Rosuvastatin titrated across its recommended dose range provides a more favorable effect on lipoprotein variables than atorvastatin, enabling more high-risk patients to achieve recommended LDL-C goals.