OBJECTIVES: Assess the cost-effectiveness of Sacubitril/Valsartan (LCZ696) versus Enalapril (ACEi) for the treatment of heart failure with reduce ejection fraction (HFrEF) from the perspective of the Chilean public healthcare system. METHODS: A patient-level Markov model was built based on data reported in the pivotal trial “PARADIGM-HF” to predict mortality, hospitalization and health-related quality of life. Expected costs were measured in Chilean pesos (1 USD = 654.07 CLP$) and benefits in quality adjusted life years (QALYs). Health related quality of life was measured in the PARADIGM-HF trial model and valuated using the Chilean tariff. A 30-year time horizon and 3% discount rate was considered for costs and outcomes. A probabilistic sensitivity analyses was performed to account for uncertainty. RESULTS: The total expected costs of treating HFrEF with LCZ696 are higher than ACEi (US$18,147 and US$7,524 respectively). Similarly, the expected incremental health benefit is higher in LCZ696 group (0.52 QALYs). The base case scenario (current market prices for all treatments) shows an average ICER of LCZ696 versus ACEi of US$33,244/QALY on all PARADIGM-HF patients and US$29,532/QALYs for the subgroup of Latin-American patients. At a suggested threshold between 1xGDP (US$22,000/QALY) and 3xGDP per capita (US$60,000/QALY), the probability of cost-effectiveness of LCZ was 23% and 92% respectively. The ICER is reduced to US$24,675 on all PARADIGM-HF patients and US$22,225 when considering the Latin-American subgroup when the price is reduced a 25%. The ICER was most sensitive to the mortality hazard ratio. CONCLUSIONS: Due to the high incremental cost, it is reasonable to explore heterogeneity in order to find the most benefited subgroup of patients.