OBJECTIVES: Cystic fibrosis (CF), the most common lethal genetic disease in Caucasians, causes a high burden of disease. Median age at death is in the late 20s with the most common mode of death being respiratory failure. Treatment with ivacaftor, a CF transmembrane conductance regulator (CFTR) protein potentiator, was generally safe and improved risk-factors for mortality in CF, including pulmonary function, weight and pulmonary exacerbations.  Since controlled clinical trials cannot directly demonstrate survival benefits, we estimated the potential for survival benefit from drug therapies based on similar, observed short-term changes to risk factors known to impact survival in CF. METHODS: Survival information for CF patients in Germany, France, the UK, and Ireland was obtained from national registries and individually fitted to a Weibull function. From these survival curves the hazard function for an average CF patient was calculated as a function of age. The impact to the hazard function from improvements in risk factors (FEV1, weight-for-age z-score, pancreatic sufficiency, diabetes, Staphylococcus aureus, Burkholderia cepacia, and annual number of pulmonary exacerbations) was estimated using previously published Cox proportional hazards model for CF mortality. RESULTS: For each country, a survival function was developed taking into account current average mortality rates and estimated long-term changes to risk factors. Sensitivity analysis suggest that it is possible for drugs that improve clinical outcomes in CF, including pulmonary function, weight and pulmonary exacerbations, to add a decade to the median life expectancy CF patients. CONCLUSIONS: Modeling suggests that therapies that improve clinical risk factors for mortality in CF, including pulmonary function, weight and pulmonary exacerbations, may extend the lives of CF patients.