Background: We performed a meta-analysis of randomized controlled trials to assess ongoing concerns about the safety profile of combination angiotensin II receptor blockers (ARBs) plus angiotensin-converting enzyme (ACE) inhibitors in symptomatic left ventricular dysfunction. Methods: MEDLINE (January 1966-December 2006) and Web sites for the National Institute of Health Clinical Trials and the Food and Drug Administration were searched for eligible RCTs that included 500 or more subjects, had a follow-up of 3 months or longer, and reported adverse effects. We used a random effects model to calculate the relative risk (RR) and 95% confidence interval (CI) for the following outcome measures: medication discontinuations because of adverse effects, worsening renal function (an increase in serum creatinine level of >0.5 mg/dL [to convert to micromoles per liter, multiply by 88.4]), hyperkalemia (serum potassium level >5.5 mEq/L [to convert to millimoles per liter, multiply by 1]), and symptomatic hypotension. Results: Four studies (N = 17 337; mean follow-up, 25 months [range, 11-41 months]) were selected. Combination ARB plus ACE inhibitor vs control treatment that included ACE inhibitors was associated with significant increases in medication discontinuations because of adverse effects in patients with chronic heart failure (RR, 1.38 [95% CI, 1.22-1.55]) or in patients with acute myocardial infarction with symptomatic left ventricular dysfunction (RR, 1.17 [95% CI, 1.03-1.34]), and for both conditions there were significant increases in worsening renal function (RR, 2.17 [95% CI, 1.59-2.97] and RR, 1.61 [95% CI, 1.31-1.98], respectively), hyperkalemia (RR, 4.87 [95% CI, 2.39-9.94] and RR, 1.33 [95% CI, 0.90-1.98], respectively; the latter was not significant), and symptomatic hypotension (RR, 1.50 [95% CI, 1.09-2.07], and RR, 1.48 [95% CI, 1.33-3.18], respectively). Conclusion: Combination ARB plus ACE inhibitor therapy in subjects with symptomatic left ventricular dysfunction was accompanied by marked increases in adverse effects.