OBJECTIVES:  The randomised controlled PARADIGM-HF trial demonstrated that sacubitril/valsartan was superior to the angiotensin-converting-enzyme inhibitor (ACEi) enalapril in reducing all-cause mortality and all-cause hospitalisations in patients with heart failure (HF) with reduced ejection fraction (EF). This was consistent across the pre-defined subgroups. Differences in mortality and all-cause hospitalisation rates between PARADIGM-HF and the UK HF population mean that absolute incremental costs and benefits (and consequently cost-effectiveness) for sacubitril/valsartan may not be generalisable. We assessed the generalisability of the cost-effectiveness of sacubitril/valsartan vs. ACEi by calibrating the cost-effectiveness model based on PARADIGM-HF to reflect UK mortality and all-cause hospitalisation rates. METHODS:  A cost-utility model was developed based on regression models of all-cause mortality, all-cause hospitalisations and EQ-5D derived from PARADIGM-HF including patient baseline characteristics as covariates. Cost-effectiveness was initially estimated for an average PARADIGM-HF patient. In alternative analyses, the cost-utility model was calibrated by varying the constant terms in the regression models of mortality and all-cause hospitalisation until the model outputs in the ACEi arm matched the all-cause mortality at Year 4 and annualised all-cause hospitalisation rate in the Clinical Practice Research Datalink (CPRD) in England and Scottish Morbidity Record (SMR) in Scotland (includes patients with preserved and reduced EF); cost-effectiveness was estimated using the calibrated model parameters. RESULTS:  In the enalapril arm of PARADIGM-HF, mortality at Year 4 and the annualised all-cause hospitalisation rate was lower than the CPRD and SMR HF population. In the analysis based on an average patient in PARADIGM-HF, sacubitril/valsartan was associated with an incremental cost-effectiveness ratio (ICER) of £17,624 per quality-adjusted life-year (QALY), while in the calibrated analyses the ICERs were £12,595 (CPRD) and £12,960 (SMR) per QALY. CONCLUSIONS:  Sacubitril/valsartan is a cost-effective treatment option vs ACEi, based on conventional willingness-to-pay thresholds (£20,000 per QALY), using mortality and hospitalisation rates from both PARADIGM-HF and real-world UK HF populations.