Objective <p>Clinical trials have demonstrated the efficacy of the sodium-glucose cotransporter-2 inhibitor (SGLT2i) empagliflozin in patients suffering from heart failure (HF), regardless of whether their left-ventricle ejection fraction (LVEF) is reduced (HFrEF), mildly reduced (HFmrEF), or preserved (HFpEF). This study aims to assess the cost-effectiveness of empagliflozin when added to standard of care (SoC), consisting of lifestyle changes, medications, and surgery or devices, compared to SoC alone in patients with chronic HF irrespective of LVEF in the Netherlands.</p> Methods <p>A Markov model was developed to simulate patient outcomes over a lifetime horizon, incorporating data from the EMPEROR-Reduced and EMPEROR-Preserved trials. Key outcomes included incremental cost-effectiveness ratios (ICERs) expressed in costs per quality-adjusted life-year (QALY) gained, life expectancy, and hospitalization rates. Probabilistic and one-way sensitivity analyses were conducted to assess the robustness of the results. </p> Results <p>The analysis revealed that treatment with empagliflozin plus SoC resulted in higher life expectancy (6.58 vs. 6.47 years for HFrEF; 7.78 vs. 7.69 years for HFmrEF/HFpEF) and a lower incidence of HF hospitalizations compared to SoC alone. The ICERs were €8515/QALY for HFrEF and €9807/QALY for HFmrEF/HFpEF, both below the willingness-to-pay threshold of €50,000/QALY, indicating cost-effectiveness. Sensitivity analyses confirmed the robustness of the results, indicating there is a high probability (97% for HFrEF and 98% for HFmrEF/HFpEF) that empagliflozin plus SoC is cost-effective.</p> Conclusion <p>Empagliflozin, when added to SoC, is a cost-effective treatment option for patients irrespective of LVEF in the Netherlands.</p>