OBJECTIVE: To estimate the cost of diabetes mellitus (DM) in Spain by reviewing all available DM cost data. METHODS: Outstanding articles and unpublished data were identified through searches of PubMed, Spanish Medical Index, Spanish databases for doctoral thesis, Ministry of Health, Carlos III Health Institute, Spanish Health Technology Assessment Agencies, SAMFYC diabetes group, Spanish Federation of Diabetes Education Societies, and other DM sources from 1966 to November 2004. All studies with outstanding information on direct or indirect costs of DM diagnosis, treatment or complications were included (cost estimates in € of 2004). RESULTS: In total, 32 cost-of-illness (COI) studies published between 1982 and 2004 met the inclusion criteria (16.354 DM patients), 23 of them were performed with the prevalence method, 1 with the incidence method and 6 were pharmacoeconomic analyses. Total annual costs of DM in Spain would range between €685 and €2.771 million (1.6-6.4% of the Spanish public health expenditure). However, those results could underestimate the real DM cost (according to CODE-2 study, the type 2 DM cost in Spain would be around 2.317 million € per year). The annual average cost per patient with DM would range between 1.627 and €3.982 for DM type-1 and €1.049-€5.091 for DM type 2. The cost of hospital admissions, primary care visits and antidiabetic treatments would be 36-58%, 7-14% and 11-13% of the total cost, respectively. The indirect costs would be 28-43% of total DM costs. DM complications costs: serious hypoglycemia (€3.469), hyperglycemia (€3.357), infections (€2.703), ketoacidosis (€2.633), stroke (€4.091), ischemic cardiac disease (€3.675), neuropathy (€3.540), nephropathy (€3.525) and retinopathy (€2.109). CONCLUSIONS: The variability in the costs estimates was due to the differences of the studies design. To estimate the real cost of DM, a well designed COI prospective study is needed.