OBJECTIVE: The 5 major classes of antihypertensive agents are suitable for the initiation and maintenance of antihypertensive therapy according to 2003 European Society of Hypertension – European Society of Cardiology guidelines. The aim of this study was to compare the cost-effectiveness of these antihypertensive agents in mild to moderate hypertension in Greece. METHODS: A Markov model, based on data from randomised trials, was developed to compare the 5 alternative interventions: chlorthalidone, propranolol, amlodipine, silazapril and losartan. A cost-effectiveness analysis was performed, based on numbers-needed-to-treat (NNT) derived from a published metaanalysis. The primary outcome measure was the NNT to prevent one fatal cardiovascular disease event and the secondary outcome measure was the NNT to prevent one stroke (fatal and nonfatal). Cost data were derived from public sources. Only direct costs were considered in the analysis. All costs were calculated from the perspective of the public insurance system organisations, in 2003 Euros. Future costs and clinical benefits were discounted at 5%. The time horizon was 5 years. Sensitivity analyses tested the effect of modifying the input parameters on the economic endpoints. RESULTS: No significant differences in efficacy presented among drug groups in mild to moderate hypertension. The NNT for 5 years to prevent one fatal cardiovascular disease event was 135.27 patients and to prevent one stroke was just 64.05 patients. The estimated total cost to prevent one fatal cardiovascular disease event was 78,121.40€, 84,040.63€, 118,825.36€, 103,098.82€, and 168,485.60€ for chlorthalidone, propranolol, amlodipine, silazapril and losartan respectively. The estimated total cost to prevent one stroke was 36,990.28€, 39,793.02€, 56,263.50€, 48,817.03€ and 79,777.50€ respectively. Sensitivity analysis confirmed the superiority of chlorthalidone against the other antihypertensive agents. CONCLUSIONS: In mild to moderate hypertension, chlorthalidone is more cost-effective than propranolol, amlodipine, silazapril and losartan and should be considered as the first choice of antihypertensive therapy.