Clinical trials for comparison of antihypertensive agents seem to greatly differ from clinical practice. One limitation of clinical trials is the absence of a random distribution of target organ damage that can determine differences in the response to a given therapy. This study was designed to evaluate, within the conditions of daily clinical practice, the capacity of four different antihypertensive drugs to control blood pressure in essential hypertensive patients randomly distributed according to an assessment of target organ damage. A group of 200 mild essential hypertensives (44.4±12.5 years old; 50.3% male) sent to our unit for routine evaluation and therapy of their hypertension were included in the study. They were randomly allocated to four different therapeutic agents (atenolol, lisinopril, nisoldipine, or losartan). There were 50 patients in each group. After a 4‐week washout of previous antihypertensive therapy, or without it if previously untreated (43 %), patients received one of the four medications in an open fashion. A random distribution was performed for sex, age, and the presence of target organ damage, including left ventricular hypertrophy determined by echocardiography, alterations (plaque or thickening) on carotid Doppler ultrasonograms, and/or the presence of microalbuminuria (>30 mg/24 h). Efficacy and tolerability were evaluated after 12 weeks of therapy. Left ventricular hypertrophy was detected in 32% of patients, diastolic dysfunction in 30.1%, and systolic dysfunction in 1.9%. Carotid plaques were detected in 41.5% of subjects, but only 10.4% had more than one plaque. Medial/intimal thickness of >1.00 mm was present in 41.5% of patients. Finally, 27% exhibited microalbuminuria. The expected correlations among the different components of target organ damage were found. After 12 weeks of therapy, blood pressure reductions were similar in all groups, and the expected goal of control (diastolic pressure of <90 mm Hg) was attained in 64.6% of atenolol patients, 68.8% on lisinopril, 62.2% on nisoldipine, and 60.8% on losartan. No severe adverse events were observed, and the withdrawal rates were 20% with atenolol, 10% with lisinopril and nisoldipine, and 8% with losartan. In conclusion, the four antihypertensive agents showed equal antihypertensive efficacy in patients with a similar degree of target organ damage. The β blocker exhibited the lowest tolerability. These results are in agreement with those obtained in prospective clinical trials.