OBJECTIVES: We assessed the cost-effectiveness of sacubitril/valsartan compared to angiotensin-converting enzyme inhibitors for the treatment of individuals with chronic heart failure (CHF) and reduced ejection fraction (HFrEF), from the Swiss healthcare system perspective. METHODS: The model was implemented as a lifelong regression-based cohort-model comparing sacubitril/valsartan with enalapril in CHF patients with HFrEF and New York Heart Association Functional Classification II-IV symptoms. Regression models based on the randomised, clinical, phase III PARADIGM-HF trial were used to predict events (all-cause mortality, hospitalisations, adverse events and quality-of-life) for each treatment strategy over the modelled life-time horizon, adjusted for patient characteristics. Alternative analyses were implemented (cardiovascular mortality based on PARADIGM-HF trial, non-cardiovascular mortality obtained from Swiss life-tables). Costs data were obtained from Swiss sources for year 2014. Costs and effects were discounted by 3%. The outcome of interest was incremental cost-effectiveness ratio (ICER), expressed as cost per quality adjusted life year (QALY) gained. Deterministic sensitivity analyses (DSA), scenario and probabilistic sensitivity analyses (PSA) established the robustness of the results. RESULTS: In the base-case analysis, the sacubitril/valsartan strategy compared to enalapril showed a decrease in number of hospitalisations (6.0%/year absolute reduction) and life-time hospital costs by 8.0% (discounted). Sacubitril/valsartan was predicted to improve overall and quality-adjusted survival by 0.50 years and 0.42 QALYs. Additional net total costs were CHF 16,204, leading to an ICER of CHF 38,091. Alternative use of Swiss life-tables led to an ICER of CHF 35,527. DSA showed that results were robust; there was sensitivity to long-term mortality assumptions, duration of treatment effect and time horizon. In PSA, the probability of sacubitril/valsartan being cost-effective at thresholds of CHF 40, 000 and CHF 50,000 was 82.0% and 96.0%. CONCLUSIONS: From the Swiss healthcare system perspective, treatment of HFrEF patients with sacubitril/valsartan versus enalapril is likely to be cost-effective, if willingness-to-pay threshold of CHF 50,000 per QALY-gained is assumed.