OBJECTIVES: Recently, the first single pill (SPC) triple-combination antihypertensive therapy with valsartan(VAL), amlodipine(AML) and hydrochlorothiazide(HCTZ) has been available. The aim of this study is to compare the cost-utility of single pill triple combination with each of the dual combinations deriving from the same components in patients with moderate to severe hypertension. This is the first study to evaluate the CUA of this SPC. METHODS: A Markov model with eight health states was constructed. The short-term effect of antihypertensive treatment on blood pressure was extrapolated through the Hellenic SCORE and Framingham risk equations in order to estimate the long-term survival and quality-adjusted life-years (QALYs). Pharmaceutical cost was extracted from the official price bulletins. Cost of adverse events was derived from international literature, reflecting €2012. Outcomes and costs were evaluated over lifetime, divided into annual cycles and were discounted at 3.0%. The analysis was conducted from a Greek third-party-payer perspective. RESULTS: The cost of treatment with triple combination was estimated at €17,499 in comparison to €18,203 for AML/VAL, €16,069 for VAL/HCTZ and €11,945 for AML/HCTZ. The QALYs of the triple combination were 12.76 vs. 12.64, 12.61 and 12.38 of double combinations respectively, resulting in incremental QALYs gained of triple vs. double combination in 0.12, 0.15 and 0.38 respectively. The incremental cost-effectiveness ratio (ICER) per QALY gained with the triple combination versus VAL/HCTZ and AML/HCTZ was far lower than the Greek GDP per capita  (9,649€, 14,581€, respectively), while the triple combination was found to be dominant in comparison with AML/VAL. Extensive sensitivity analyses proved the robustness of the results. With a probability of exceeding 90%, the triple combination is cost effective with an incremental cost effectiveness ratio (ICER) threshold of less than 20,000 €/QALY.  CONCLUSIONS: The single pill triple combination therapy with AML/VAL/HCTZ is a highly cost-effective antihypertensive choice for the treatment of moderate to severe hypertension.