Background: Renin-angiotensin-aldosterone system(RAAS) blockers are effective therapies for heart failure and reduced ejection fraction (HFrEF) or left ventricular dysfunction (LVD). We aimed to assess the efficacy and safety of RAAS blockers in these patients. Methods: We searched MEDLINE, EMBASE, and Cochrane Library in May 2015. Twenty-one double-blind randomized controlled trials (RCTs) with 69,229 patients were included this network meta-analysis. Results: Compared with placebo, an angiotensin receptor-neprilysin inhibitor (ARNI) had the highest probability of reducing all-causemortality (odds ratio [OR] = 0.67, 95% credible interval [CrI]: 0.48-0.86), followed by an aldosterone receptor antagonist (ARA, OR = 0.74, 95% CrI: 0.62-0.88) and an angiotensin-converting enzyme inhibitor (ACEI, OR = 0.80, 95% CrI: 0.71-0.89). The most efficacious therapy for preventing heart failure hospitalization was ARNI (OR = 0.55, 95% CrI: 0.40-0.71), followed by combination therapy with an angiotensin II receptor blocker (ARB) plus an ACEI (OR = 0.61, 95% CrI: 0.49-0.75), then an ACEI alone (OR = 0.69, 95% CrI: 0.61-0.77). Sensitivity analysis restricted to nine RCTs with a high background use of ACEI and/or ARB (>80%) indicated that adding an ARA to current standard therapy significantly reduced mortality (OR = 0.73, 95% CrI: 0.51-0.95) and hospitalization risk (OR = 0.67, 95% CrI: 0.47-0.87), but did not significantly increase the discontinuation risk (OR = 1.29, 95% CrI: 0.83-2.31). Conclusions: ARNI has the highest probability of being the most efficacious therapy for HFrEF in reducing death and hospitalization for heart failure. ARA has the most favorable benefit-risk profile as an adjunct to background ACEI and/or ARB therapy. (C) 2015 Elsevier Ireland Ltd. All rights reserved.