OBJECTIVES: Type 2 diabetes mellitus (DM2) patients are at long-term risk of cardiovascular events and of microvascular complications that contribute to the burden of the disease. The objective is to identify the main factors directly associated to costs of DM2 care in Spain. METHODS: A systematic review of cost of disease studies published in English or Spanish between January 2001 and December 2011. A search of electronic databases [international and national] and hand search of reference lists of key publications was performed. A methodological quality assessment of reviewed publications applying the Center for Evidence Based Medicine (CEBM, 2012) tool was performed. All costs updated to €, 2011. RESULTS: A total of 1505 articles were identified, 639 were excluded and 28 were retrieved. Total national healthcare expenditure intended for DM2 care in Spain was about €2,800 million per year. Direct costs varied between €851.23 and €4,882.80 per patient/year. Main cost drivers were: other pharmacological treatments different from antidiabetics (37.83%), hospital admissions (31.93%), medical visits (25.57%), and oral antidiabetics (4.67%). Severe and moderate hypoglycemias increased costs 174 and 8 times, respectively, compared to those episodes with no need of medical care. DM2 costs increased by 59.5% if the goal of HbA1c<7% was not reached; by 30% with obesity, and by 64.5% if disease related complications appeared. Each 10% raise in adherence to oral antidiabetic treatment represented a 2% to 4% reduction in DM2 costs. Levels of CEBM recommendation were 2c (16 studies), 3b (8 studies) and 4 (4 studies). CONCLUSIONS: Main factors directly associated to costs of DM2 care in Spain were hypoglycemia, DM2 related complications, HbA1c control, obesity and treatment adherence. Strategies aimed to improve these factors would have a major impact on costs reduction.