Objective:The aim of this study was to determine the cost-effectiveness of adding empagliflozin to the standard of careversusSoC alone for the treatment of patients with heart failure (HF) with reduced ejection fraction (HFrEF) from the perspective of the Ministry of Health of Malaysia.Methods:A cohort-based transition-state model, with health states defined as Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) quartiles and death, was used to determine the lifetime direct medical costs and quality-adjusted life years (QALYs) for both treatment groups. The risks of all-cause death, cardiovascular death, and health state utilities were estimated from the EMPEROR-Reduced trial. The incremental cost-effectiveness ratio (ICER) was assessed against the cost-effectiveness threshold (CET) as defined by the country’s gross domestic productper capita(RM 47,439 per QALY) to determine cost-effectiveness. Sensitivity analyses were conducted to assess the key model parameters’ uncertainty in respect to the incremental cost-effectiveness ratio. A scenario analysis was performed using health states as defined by the New York Heart Association classes.Results:Compared to SoC alone, empagliflozin + SoC for the treatment of HFrEF was more expensive (RM 25,333 vs. RM 21,675) but gained more health utilities (3.64 vs. 3.46), resulting in an ICER of RM 20,400 per QALY in the KCCQ-CSS model. A NYHA-based scenario analysis generated an ICER of RM 36,682 per QALY. A deterministic sensitivity analysis confirmed the robustness of the model in identifying the empagliflozin cost as the main driver of cost-effectiveness. The ICER was reduced to RM 6,621 when the government medication purchasing prices were used. A probabilistic sensitivity analysis with a CET of 1xGDPper capitareached 72.9% probability for empagliflozin + SoC against SoC being cost-effective.Conclusion:Empagliflozin + SoC compared to SoC alone for the treatment of HFrEF patients was cost-effective from the perspective of the MoH of Malaysia.