To compare six antihypertensive interventions for the treatment of mild hypertension. Randomized, double-blind, placebo-controlled clinical trial. Four hypertension screening and treatment centers in the United States. Hypertensive men and women, aged 45 to 69 years, with diastolic blood pressure less than 100 mm Hg. Sustained nutritional-hygienic advice to all participants to reduce weight, dietary sodium intake, and alcohol intake, and increase physical activity. Participants were randomly allocated to take (1) placebo (n=234); (2) chlorthalidone (n=136); (3) acebutolol (n=132); (4) doxazosin mesylate (n=134); (5) amlodipine maleate (n=131); or (6) enalapril maleate (n=135). Blood pressure, quality of life, side effects, blood lipid levels and analysis of other serum components, echocardiographic and electrocardiographic changes, and incidence of cardiovascular events over an average of 4.4 years of follow-up. Blood pressure reductions were sizable in all six groups, and were significantly greater for participants assigned to drug treatment than placebo ( — 15.9 vs — 9.1 mm Hg for systolic blood pressure and — 12.3 vs —8.6 mm Hg for diastolic blood pressure; p<.0001). After 4 years, 59% of participants assigned to placebo and 72% of participants given drug treatment continued on their initial medication as monotherapy. A smaller percentage of participants assigned to the drug-treatment groups died or experienced a major nonfatal cardiovascular event than those assigned to the placebo group (5.1% vs 7.3%; P=.21). After including other clinical events, the percentage of participants affected was 11.1% for those in the drug-treatment groups and 16.2% for those in the placebo group (P=.03). Incidence rates of most resting electrocardiographic abnormalities were lower and quality of life was improved more for those assigned to drug-treatment groups rather than the placebo group. Differences among the five drug treatments did not consistently favor one group in terms of regression of left ventricular mass, blood lipid levels, and other outcome measures. As an initial regimen, drug treatment in combination with nutritional-hygienic intervention was more effective in preventing cardiovascular and other clinical events than was nutritional-hygienic treatment alone. Drug-treatment group differences were minimal. Pending results from large-scale clinical trials to evaluate drug treatments for their effect on cardiovascular clinical events, these findings support the recommendations of the new fifth Joint National Committee report regarding treatment choices for people with stage 1 ("mild") hypertension. © 1993, American Medical Association. All rights reserved.