Background: In September 2014, the PARADIGM-HF trial showed the heart failure drug combination sacubitril/valsartan to be superior to enalapril for patients with a reduced ejection fraction. Objectives: To determine the incremental cost-effectiveness of sacubitril/valsartan compared with enalapril in the Netherlands using the clinical data from the PARADIGM-HF trial. Methods: To compare sacubitril/valsartan and enalapril in a cost-effectiveness study, a Markov model was developed using the effectiveness data from the PARADIGM-HF trial. A health care payer's perspective was applied in the economic evaluation. The developed model was used to evaluate the costeffectiveness for sacubitril/valsartan at different per diem prices. Results: The base-case analysis showed that sacubitril/valsartan can be cost-effective at maximum daily costs of (sic)5.50 and (sic)14.14 considering willingness-to-pay thresholds of (sic)20,000 and (sic)50,000 per quality-adjusted life-year (QALY), respectively. Sensitivity analysis demonstrated the robustness of the model, identifying only the price of sacubitril/valsartan and the mortality within the sacubitril/valsartan group as significant drivers of the cost-effectiveness ratio. Sacubitril/valsartan was cost-effective at a willingness-to-pay threshold of (sic)20,000 per QALY ((sic)50,000 per QALY) in more than 80% of the replications with certainty at the price point of(sic) ((sic)10). Conclusions: Sacubitril/valsartan can be considered a cost-effective treatment at a daily price of 5.25. Unless priced lower than enalapril (