OBJECTIVES: The aim of this study was to assess the direct costs associated to type I and II diabetes mellitus (DM) from a healthcare perspective in Spain. METHODS: We performed a cost of illness study considering the prevalence approach. The use of resources was estimated from the existing Spanish healthcare databases and bibliographic references. Costs evaluated were: hospital costs (including outpatient care), primary care costs, drugs costs, consumables costs and additional tests costs. All costs were updated to 2012 euros. RESULTS: The total direct annual cost of DM was 5,809 million euros representing 8.2% of the total Spanish health expenditure. The total drug cost accounted for 2,232 million euros (38%) and was mainly due to the elevated contribution of non-antidiabetic drugs (24%). Hospital costs represented 1,934 million € (33%) and were mainly driven by the acute and chronic complications (17%). Cardiovascular disease cost (521 million €) and peripheral vascular disease costs (127 million €) were the most important complications cost drivers. The contribution of monitoring strips to the total cost was only 118 million € (2%). Total complications cost represented 2,143 million € (37% of the total direct cost). CONCLUSIONS: DM total direct costs are strongly conditioned by DM complications cost and have a considerable economic impact on Spanish health expenditure. In order to reduce the health and economic impact generated by DM, the introduction of measures and strategies focused on improving the efficiency of the treatment of the disease are crucial.