OBJECTIVES: Despite relevant treatments, only 29% of type 2 diabetes (T2DM) patients in Greece achieve their pre-defined glycemic targets. When treatment with metformin (MF) fails to control T2DM patients, add-on therapies are needed. Sitagliptin is indicated as second-line therapy in Greece, after treatment with MF has failed and is a valid option in the proposed national therapeutic protocols. The present study aimed to assess the cost-effectiveness of adding Sitagliptin to MF vs adding sulphonylurea (SU) to MF for the treatment of T2DM patients with inadequate glycemic control. METHODS: A published individual-level simulation model was developed to simulate the lifetime medical cost, diabetic complications, drug-related adverse events, life expectancy and quality adjusted life years (QALYs) associated with Sitagliptin add-on therapy versus SU add-on therapy. The model is developed based upon the UKPDS 68 risk equations to project long-term complications and mortalities. Efficacy and safety profiles of drugs were obtained from a head-to-head trial. Costs (€ 2014 prices) and effects were discounted at 3.5% annually. Greek data retrieved by an expert input forum of specialists. Sensitivity analyses performed on 17 parameters. Analysis based on Greek payer perspective. RESULTS: Sitagliptin strategy is projected to cost 359 EUR more than SU strategy per patient over lifetime. Sitagliptin showed reductions in diabetes-related complications and adverse events. The incremental QALY for Sitagliptin strategy is 0.042, primarily driven by the improved outcomes associated with hypoglycemia, body weight change, and MI. The incremental cost effectiveness ratio (ICER) is 8,582 €/QALY gained. Sensitivity analysis conducted varied multiple parameters. ICER ranges from 4,873 to 12,173 €/QALY gained. The results are robust and never exceeded the 30,000€/QALY threshold. CONCLUSIONS: Sitagliptin add-on strategy could be cost-effective, compared to SU, for the Greek healthcare setting. Furthermore, it remains cost-effective in all types of sensitivity analysis.