Introduction: Diabetes Mellitus (DM) is a chronic-degenerative disease associated with a high risk of chronic complications and co-morbidities. However, very few data are available on the associated cost. The objective of this study is to identify the available information on the epidemiology of the disease and estimate the average annual cost incurred by the National Health Service (NHS) and society for the treatment of diabetes in Italy. Methods: A probabilistic prevalence Cost of Illness model was developed in order to calculate an aggregate measure of the economic burden associated with the disease, in terms of direct medical costs (drugs, hospitalizations, monitoring and adverse events) and indirect costs (absenteeism and early retirement). A systematic review of the literature was conducted to determine both the epidemiological and economic data. Furthermore, a one-way and probabilistic sensitivity analysis with 5,000 Monte Carlo simulations was performed, in order to test the robustness of the results and define a 95% CI. Results: The model estimated a prevalence of 2.6 million of patients under drug therapies in Italy. The total economic burden of diabetic patients in Italy amounted to € 20.3 billion/year (95% CI 95%: € 18.61 - € 22.29 billion), 54% of which are associated with indirect costs (95% CI :€ 10.10 - € 11.62 billion) and 46% with direct costs only (95% CI: € 8.11 - € 11.06 billion). Conclusions: This is the first study being conducted in Italy aimed at estimating direct and indirect cost of diabetes with a probabilistic prevalence approach. As it might be expected, the lack of information involves that the real burden of Diabetes is partly underestimated, especially with regard to indirect costs. However, this is a useful approach for policy makers, in order to understand the economic implications of the diabetes treatment in Italy. Running head: Cost of Illness of Diabetes in Italy