OBJECTIVES: To analyse the cost-effectiveness of dapagliflozin in combination with metformin in the treatment of type 2 diabetes (T2DM) in comparison with sulfonylureas, thiazolidinediones and DPP4 inhibitors also combined with metformin in Spain. METHODS: The analysis was based on the results of the available clinical trials in order to estimate the quality-adjusted life years (QALY) and economic consequences of managing the disease and its complications. An economic model was used to simulate the natural history of 10,000 T2DM patients with each treatment option. The analysis was performed from the National Health System perspective considering direct costs (pharmacological costs, adverse events, T2DM complications, hypoglycaemias and costs related to weight gain) and patient's entire life as time horizon. A discount rate of 3% was applied to costs and benefits. All costs were updated to €2013. RESULTS: The primary analysis compared dapagliflozin with sulfonylureas resulting in 0.525 additional QALYs and €1,835 additional cost (cost-effectiveness ratio of €3,496/QALY). The higher drug cost of dapagliflozin was partially offset by lower costs of complications, hypoglycemia and the cost associated with weight gain. In the secondary analyses, dapagliflozin was a cost-effective option compared with thiazolidinediones and DPP4, resulting in a cost per QALY gained of €20,183 and €487, respectively. The univariate and probabilistic sensitivity analyses confirmed the robustness of the results. CONCLUSIONS: Dapagliflozin in combination with metformin proved to be a cost-effective alternative compared to sulfonylureas, thiazolidinediones and DPP4 inhibitors in the treatment of T2DM.