OBJECTIVES The aim of the study was to assess the comparative efficacy of recommended treatment for chronic heart failure with reduced ejection fraction in terms of all-cause mortality based on a network met-analysis (NMA) of randomized controlled trials (RCTs) and to explore the impact of alternative treatment classifications depending on concomitant treatments. METHODS A systematic literature search identified 56 relevant RCTs (1980-2013) that reported mortality data that were synthesized using a Bayesian Poisson regression NMA model. Treatments were classified as angiotensin converting enzyme inhibitors (ACEI), beta-blockers (BB), angiotensin II receptor blockers (ARB), mineralocorticoid/aldosterone receptor antagonists (MRA) and the I_fchannel inhibitor (IF) ivabradine. Analysis 1 classified treatments according to the main drugs of interest, whereas Analysis 2 defined treatments according to the main drugs of interest as well as the concomitant treatments belonging to classes of interest if more than 50% of patients were taking concomitant drugs. RESULTS Six regimens were compared in Analysis 1 and 10 regimens were compared in Analysis 2.  Analysis 1 resulted in the following rate ratios (RR) versus placebo: ACEI: 0.81 (95% Credible Interval 0.61, 0.95); BB: 0.71 (0.60, 0.80); ARB: 0.90 (0.75, 1.02); ACEI+BB: 0.48 (0.30, 0.76). Analysis 2 resulted in the following RRs versus placebo: ACEI: 0.81 (0.68, 0.95); BB: 0.57 (0.35, 0.87); ARB: 0.81 (0.61, 1.01); ACEI+BB: 0.61 (0.54, 0.68). The treatments that are expected to be most efficacious depended on the treatment classification: Analysis 1 supported ACEI+BB and BB, whereas Analysis 2 supported ACEI+BB+MRA+IF and ACEI+BB+MRA [RR: 0.44 (0.34, 0.58) and 0.48 (0.38, 0.60), respectively]. CONCLUSIONS Combination treatments were likely to be more efficacious than monotherapy and adding a class to a regimen was likely to make it more efficacious regardless of the approach. However, treatment classifications affect the results and interpretation. The approach that accounts for concomitant treatments is preferred.