Context: Antihypertensive therapy is well established to reduce hypertension related morbidity and mortality, but the optimal first step therapy is unknown. OBJECTIVE: To determine whether treatment with a calcium channel blocker or an angiotensin converting enzyme inhibitor lowers the incidence of coronary heart disease (CHD) or other cardiovascular disease (CVD) events vs treatment with a diuretic. DESIGN: The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double blind, active controlled clinical trial conducted from February 1994 through March 2002. Setting and participants: A total of 33357 participants aged 55 years or older with hypertension and at least 1 other CHD risk factor from 623 North American centers. INTERVENTIONS: Participants were randomly assigned to receive chlorthalidone, 12.5 to 25 mg/d (n = 15255); amlodipine, 2.5 to 10 mg/d (n = 9048); or lisinopril, 10 to 40 mg/d (n = 9054) for planned follow up of approximately 4 to 8 years. Main outcome measures: The primary outcome was combined fatal CHD or nonfatal myocardial infarction, analyzed by intent to treat. Secondary outcomes were all cause mortality, stroke, combined CHD (primary outcome, coronary revascularization, or angina with hospitalization), and combined CVD (combined CHD, stroke, treated angina without hospitalization, heart failure [HF], and peripheral arterial disease). Results: Mean follow up was 4.9 years. The primary outcome occurred in 2956 participants, with no difference between treatments. Compared with chlorthalidone (6 years rate, 11.5%), the relative risks (RRs) were 0.98 (95% CI, 0.90-1.07) for amlodipine (6 years rate, 11.3%) and 0.99 (95% CI, 0.91-1.08) for lisinopril (6 years rate, 11.4%). Likewise, all cause mortality did not differ between groups. Five years systolic blood pressures were significantly higher in the amlodipine (0.8 mm Hg, P =.03) and lisinopril (2 mm Hg, P <.001) groups compared with chlorthalidone, and 5 years diastolic blood pressure was significantly lower with amlodipine (0.8 mm Hg, P <.001). For amlodipine vs chlorthalidone, secondary outcomes were similar except for a higher 6 years rate of HF with amlodipine (10.2% vs 7.7%; RR, 1.38; 95% CI, 1.25-1.52). For lisinopril vs chlorthalidone, lisinopril had higher 6 years rates of combined CVD (33.3% vs 30.9%; RR, 1.10; 95% CI, 1.05-1.16); stroke (6.3% vs 5.6%; RR, 1.15; 95% CI, 1.02-1.30); and HF (8.7% vs 7.7%; RR, 1.19; 95% CI, 1.07-1.31). Conclusion: Thiazide type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive. They should be preferred for first step antihypertensive therapy