BACKGROUND In GALACTIC-HF (Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure) (n = 8,256), the cardiac myosin activator, omecamtiv mecarbil, significantly reduced the primary composite endpoint (PCE) of time-to-first heart failure event or cardiovascular death in patients with heart failure and reduced ejection fraction (EF) (<= 35%). OBJECTIVES The purpose of this study was to evaluate the influence of baseline EF on the therapeutic effect of omecamtiv mecarbil. METHODS Outcomes in patients treated with omecamtiv mecarbil were compared with placebo according to EF. RESULTS The risk of the PCE in the placebo group was nearly 1.8-fold greater in the lowest EF (<= 22%) compared with the highest EF (>= 33%) quartile. Amongst the pre-specified subgroups, EF was the strongest modifier of the treatment effect of omecamtiv mecarbil on the PCE (interaction as continuous variable, p = 0.004). Patients receiving omecamtiv mecarbil had a progressively greater relative and absolute treatment effect as baseline EF decreased, with a 17% relative risk reduction for the PCE in patients with baseline EF <= 22%(n = 2,246; hazard ratio: 0.83; 95% confidence interval: 0.73 to 0.95) compared with patients with EF >= 33% (n =1,750; hazard ratio: 0.99; 95% confidence interval: 0.84 to 1.16; interaction as EF by quartiles, p = 0.013). The absolute reduction in the PCE increased with decreasing EF (EF <= 22%; absolute risk reduction, 7.4 events per 100 patient-years; number needed to treat for 3 years = 11.8), compared with no reduction in the highest EF quartile. CONCLUSIONS In heart failure patients with reduced EF, omecamtiv mecarbil produced greater therapeutic benefit as baseline EF decreased. These findings are consistent with the drug's mechanism of selectively improving systolic function and presents an important opportunity to improve the outcomes in a group of patients at greatest risk. Published by Elsevier on behalf of the American College of Cardiology Foundation.