This prospective, randomized trial evaluated the effect of monotherapy and different combination therapies on cardiovascular target organ damage and metabolic profile in 520 hypertensive patients. Patients were allocated to a single agent: carvedilol 25 mg, amlodipine 10 mg, enalapril 20 mg, or losartan 50 mg (groups C, A, E, and L, respectively). After 2 months (level 2), nonresponders received a low-dose thiazide diuretic, and after 4 months (level 3), amlodipine (groups E, C, and L) and carvedilol (group A). Twenty-four-hour blood pressure was significantly lowered in all treatment groups. Blood pressure control was more pronounced in patients receiving two or three drugs. At the end of the study, the carotid intima-media thickness decreased in group L (P<.01), left ventricular mass index in groups E and L (P<.05 and P<.001, respectively), with a concomitant reduction in cholesterol in group L (P<.03). Diastolic function improved significantly in group L (P<.05). This study describes the need to control blood pressure with two or more drugs in most hypertensive patients and illustrates good clinical outcomes, independent of blood pressure lowering, using combination therapy with losartan, low-dose thiazide, and amlodipine.