OBJECTIVES: The economic burden of congenital hyperinsulinism (CHI)—a rare genetic disease causing persistent hypoglycaemia, typically in newborns—has not been well-studied or reported. In patients with the diffuse variant of the disease, management often involves near-total surgical removal of the pancreas, leading to type 1 diabetes mellitus (T1DM) in later life. The aim of this study was to estimate the cost of illness (COI) from a service provider perspective (National Health Service, NHS) of all CHI patients in the UK, and to explore the distribution of the COI within CHI. METHODS: The model was based on standard practice of two centres of excellence in CHI. Model inputs were informed by a pragmatic literature review in conjunction with NHS Reference Costs and the British National Formulary (2014–2015). Only direct costs to the NHS were considered. A prevalence-based approach was used and annual costs incurred at all ages were calculated. A deterministic sensitivity analysis (DSA) was run at 5% to identify major cost drivers. RESULTS:  In total, the COI of all patients with CHI to the NHS was £4,561,827.58 per year. The average cost per patient was £1,468.24. The distribution of costs was skewed among CHI patients, with just 3.1% of all CHI patients (95 patients in their first year of life) contributing to 42.1% (£1,919,751.79) of the total costs. Results from the DSA identified lack of response to first-line therapy, and the development of T1DM post-surgery (and the associated healthcare costs) as major cost drivers in the model. CONCLUSIONS:  Despite being a rare disease, the annual cost of CHI to the NHS was found to be substantial. Development and management of post-surgical T1DM as a major cost driver highlights the need for effective treatments which could potentially mitigate such consequences and costs.