The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) provides a unique opportunity to compare the long-term relative safety and efficacy of angiotensin-converting enzyme inhibitor and calcium channel blocker-initiated therapy in older hypertensive individuals. Patients were randomized to amlodipine (n=9048) or lisinopril (n=9054). The primary outcome was combined fatal coronary heart disease or nonfatal myocardial infarction, analyzed by intention-to-treat. Secondary outcomes included all-cause mortality, stroke, combined cardiovascular disease (CVD), end-stage renal disease (ESRD), cancer, and gastrointestinal bleeding. Mean follow-up was 4.9 years. Blood pressure control was similar in nonblacks, but not in blacks. No significant differences were found between treatment groups for the primary outcome, all-cause mortality, ESRD, or cancer. Stroke rates were higher on lisinopril in blacks (RR=1.51, 95% CI 1.22 to 1.86) but not in nonblacks (RR=1.07, 95% CI 0.89 to 1.28), and in women (RR=1.45, 95% CI 1.17 to 1.79), but not in men (RR=1.10, 95% CI 0.92 to 1.31). Rates of combined CVD were higher (RR=1.06, 95% CI 1.00 to 1.12) because of higher rates for strokes, peripheral arterial disease, and angina, which were partly offset by lower rates for heart failure (RR=0.87, 95% CI 0.78 to 0.96) on lisinopril compared with amlodipine. Gastrointestinal bleeds and angioedema were higher on lisinopril. Patients with and without baseline coronary heart disease showed similar outcome patterns. We conclude that in hypertensive patients, the risks for coronary events are similar, but for stroke, combined CVD, gastrointestinal bleeding, and angioedema are higher and for heart failure are lower for lisinopril-based compared with amlodipine-based therapy. Some, but not all, of these differences may be explained by less effective blood pressure control in the lisinopril arm.