OBJECTIVES: To evaluate the long-term cost-effectiveness of exenatide once-weekly (ExQW) versus insulin glargine (IG) or liraglutide 1.2 mg (Lira1.2mg) for the treatment of adult patients with Type 2 diabetes mellitus (T2DM) not adequately controlled on oral antidiabetic drug (OAD) therapy in Greece. METHODS: The published and validated CARDIFF diabetes model was used to project clinical and economic outcomes over a patient’s lifetime. Treatment effects and patient baseline characteristics were retrieved from a head-to-head randomized clinical trial (DURATION 3) and a published network meta-analysis comparing ExQW with IG and Lira1.2mg, respectively. Following a Greek third-party payer perspective, direct medical costs related to drug acquisition, consumables, fatal and non-fatal developed micro- and macro-vascular complications, maintenance treatment, as well as treatment-related adverse events were considered (€ 2016). Resource consumption associated with each treatment was based on expert advice. Cost units and utility data were extracted from literature and publicly available official sources and assigned to model parameters to calculate total quality-adjusted life years (QALYs) and total costs as well as incremental cost-effectiveness ratios (ICERs). Sensitivity analyses explored the impact of changes in input data. RESULTS: Over a patient’s lifetime, ExQW was associated with 0.458 and 0.039 incremental QALYs and €2,061 and €110 incremental costs compared with IG and Lira1.2mg, respectively. The corresponding ICERs were €4,499 and €2,827 per QALY gained versus the treatment with IG and Lira1.2mg, respectively. One-way sensitivity analysis confirmed ExQW’s cost-effective profile. At the defined willingness-to-pay threshold of €36,000 per QALY gained, probabilistic sensitivity analysis showed that ExQW was estimated to have a 100% and 88.2% probability of being cost-effective relative to IG and Lira1.2mg, respectively. CONCLUSIONS: ExQW was estimated to be cost-effective relative to IG and Lira1.2mg for the treatment of T2DM in adults not adequately controlled on OAD therapy in Greece.