A number of major clinical trials have demonstrated the clinical benefits of lowering blood pressure and have indicated that a majority of patients with hypertension will require more than one drug to achieve optimal blood pressure control. However, there is little data showing which antihypertensive combination best protects patients from cardiovascular events and which best achieves the target blood pressure with the fewest adverse events. The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial is the first large-scale investigator-initiated multicenter study with a prospective, randomized, open, blinded endpoint evaluation (PROBE) design to directly compare cardiovascular mortality and morbidity, incidence of adverse drug reaction, and degree of blood pressure reduction in Japanese hypertensive patients for a combination of angiotensin receptor blockers, beta-blockers or thiazide diuretics in addition to a calcium antagonist, benidipine hydrochloride, with a response-dependent dose titration scheme. The COPE trial is being conducted with the cooperation of more than 100 centers and clinics in Japan and involves 3,000 patients, who will be followed for 3 years. Eligible patients are being enrolled from May 2003 until May 2006. Results from the COPE trial should provide new evidence for selecting optimal combination therapies for hypertensive patients.