OBJECTIVES: Diabetes Mellitus (DM) is a chronic-degenerative disease associated with a high risk of chronic complications and co-morbidities. The aim of this study is to estimate the average annual cost incurred by the National Health Service (NHS) for the treatment of DM stratified by patients’ comorbidities. Moreover, the model estimate the economic impact implementing good clinical practice for the management of diabetic patients. METHODS: Data were extrapolated from administrative database of the Marche Region and specific inclusion and exclusion criteria were developed from clinical board in order to estimate patients with DM only, DM+1, DM+2, DM+3 and DM+4 comorbidities (cardiovascular disease, neuropathy, nephropathy and retinopathy). Regional data were considered a good proxy for implementing a previous developed Cost of Illness model from NHS perspective already published. Scenario analysis were considered to estimate the economic impact of good clinical practice implementation in the treatment of DM and its comorbidities in Italy. RESULTS: The model estimated an average number of diabetic patients per year in the Marche region of 86.155 (5.5% of population) from 2008-2011. Mean costs per patients with DM only, DM+1, DM+2, DM+3 and DM+4 comorbidities were € 179, € 1,560, € 2,736, € 8,494 and € 21,321, respectively. From the NHS perspective, the total economic burden of DM in Italy amounted to € 8.5 billion/year (22% for drugs, 74% for hospitalization and 4% for visits). Scenario analysis demonstrate that implementation of good clinical practice could save over € 700 million year. CONCLUSIONS: This model is the first study that consider real world data and CoI model to estimate the economic burden of DM and its comorbidities from the NHS perspective. Integrated management of the diabetic patient could be a good driver for the reduction of the costs of this disease in Italy.