OBJECTIVES: The first single-pill triple antihypertensive therapy with valsartan(VAL), amlodipine(AML) and hydrochlorothiazide(HCTZ) is currently available. The aim of this study was to compare the cost-effectiveness of the single-pill triple combination with dual components in generic forms.  METHODS:  A Markov model evaluating the cost-effectiveness of the single-pill triple combination against each of the dual components was constructed.  Two important assumptions have been considered i) the cheaper available generics ii) effectiveness and adverse-events were the same as in the original forms. To achieve the lowest available price for the generic alternatives, three pills were necessary for the combination AML/VAL, three for VAL/HCTZ and two for AML/HCTZ. It was also assumed that adherence and Quality of Life (QoL) were similar as with single pill dual components. The time horizon was lifetime. Effectiveness and costs were discounted at 3% rate. The analysis was conducted from Greek third-party-payer perspective, in 2012(€) RESULTS:  The triple combination was expected to increase life expectancy by 0.14 to 0.49 years and QALYs by 0.12 to 0.38, comparing with its dual components. The total cost of treatment with triple combination was estimated at €17,499 in comparison to €16,521 for AML/VAL, €14,959 for VAL/HCTZ and €11,269 for AML/HCTZ. The incremental cost-effectiveness ratio (ICER) per Quality Adjusted Life Year (QALY) gained with the triple combination versus the dual combinations VAL/AML, VAL/HCT and AML/HCTZ was 13,251€, 28,067€ and 16,541€. There was a probability of more than 80% for the triple combination to be cost-effective with an incremental cost effectiveness ratio (ICER) threshold of 25,000€/QALY gained. CONCLUSIONS: The single-pill triple combination therapy with VAL/AML/HCTZ is a cost-effective antihypertensive choice, compared to its dual components in generic forms. Moreover, this study may underestimate the cost-effectiveness of the triple combination since a single-pill formulation would improve treatment adherence and effectiveness more than the other comparators, requiring 2 to 3 different pill intake.