BACKGROUND: Trials comparing hypertension monotherapies have found either no difference or modest differences in blood pressure (BP) and cardiovascular events. However, no trial has assessed the comparative effectiveness of 2nd-line therapy in patients whose BP was not controlled with a thiazide diuretic. METHODS AND RESULTS: This was an observational study conducted with a hypertension registry of adults enrolled in 3 large integrated health care delivery systems from 2002 to 2007. Patients newly started on thiazide monotherapy whose BP remained uncontrolled were observed after addition of either an angiotensin-converting enzyme (ACE) inhibitor or beta-blocker for subsequent BP control and cardiovascular events. Patients for whom either add-on drug was indicated or contraindicated were excluded. After adjustment for patient characteristics and study year, BP control during the subsequent 6 to 18 months was comparable for the 2 agents (70.5% ACE, 69.0% beta-blockers; P=0.09). Rates of incident myocardial infarction (hazard ratio, 1.05; 95% confidence interval, 0.69 to 1.58) and stroke (hazard ratio, 1.01; 95% confidence interval, 0.68 to 1.52) were also similar for the ACE inhibitor and beta-blocker groups during an average of 2.3 years of follow-up. There were also no differences in heart failure or renal function. CONCLUSIONS: ACE inhibitors and beta-blockers are equally effective in lowering BP and preventing cardiovascular events for patients whose BP is not controlled with a thiazide diuretic alone and who have no compelling indication for a specific 2nd-line agent.