OBJECTIVE: Indapamide is one of the most frequently prescribed diuretics in Greece and the most expensive too. The purpose of this study was to compare the cost-effectiveness of indapamide with propranolol, amlodipine, enalapril and irbesartan in the management of mild-to-moderate hypertension in Greece. METHODS: A cost-effectiveness analysis was performed from a third-party payer perspective, in 2004 Euros (€). A decision analysis model was developed to compare the five alternative interventions. Clinical inputs were derived from randomized controlled trials and cost data from public sources. The evaluation of the cost of managing hypertension includes the cost of drug therapy, monitoring, treating side-effects, poor compliance and switching. The DerSimonian and Laird method was used for the meta-analysis. The time horizon was five years. Future costs and health benefits were discounted at 5%. Extensive sensitivity analyses were performed. RESULTS: Old and new drugs provided similar protection against total mortality and major CVD events in mild-to-moderate uncomplicated hypertension. The five-years total treatment cost was €550.99, €582.04, €864.32, €622.30, and €1283.99 for indapamide, propranolol, amlodipine, enalapril and irbesartan respectively and the estimated total cost to prevent one major cardiovascular event was €16,239.77, €17,154.91, €25,474.88, €18,341.68 and €37,844.09 respectively. Sensitivity analyses confirmed the lower cost-effectiveness ratio of indapamide in comparison with propranolol, amlodipine, enalapril or irbesartan. CONCLUSION: In the management of mild-to-moderate hypertension in Greece, indapamide is more cost-effective than propranolol, amlodipine, enalapril or irbesartan. The results of this study support the last recommendations of the Joint National Committee and the International Society of Hypertension. Indapamide should be considered as the first choice of antihypertensive treatment in uncomplicated hypertension.