OBJECTIVES: To calculate the cost of illness (COI) associated with adrenal insufficiency (AI) in the UK. AI patients do not produce cortisol and require glucocorticoid replacement therapy (RT) to survive, which is predominantly immediate-release hydrocortisone in the UK. With current therapy, AI patients have increased morbidity and premature mortality, and suffer reduced quality-of-life. METHODS: The COI determines the direct and indirect costs over a 1-year period. The COI includes the cost of RT, primary and secondary care costs (GP and outpatient appointments; admissions for adrenal crises; diagnosis and management of AI) and those associated with reduced productivity (absenteeism). Direct costs were estimated using national reference costs, Payment by Results tariffs and other published data. AI prevalence and adrenal crises data were taken from published literature and activity data (hospital admissions for management of AI) from Hospital Episode Statistics (HES) data. A 2012 worldwide survey of AI patients was used to determine days taken off work and clinical expert opinion was sought to determine total outpatient appointments per year. The costs associated with premature mortality, the treatment and management of co-morbidities and the burden associated with reduced quality of life were not included due to lack of data. RESULTS: There are ~20,000 AI patients in the UK. Based upon the burden of disease calculations, the estimated COI associated with AI is £1,922 per patient or £39.7 million over 1 year: RT, £21.7 million; GP appointments, £1.8 million; secondary care, £4.4 million; and reduced productivity, £11.8 million. CONCLUSIONS: The high healthcare and social costs associated with AI highlight the clinical and economic need to improve RT. Indeed, as some consequences of the disease were not included in the calculations, £39.7 million is likely a considerable underestimate of the true burden of disease.