The aim of this study was to compare the cost-utility of the first available single-pill triple combination antihypertensive therapy containing valsartan (V), amlodipine (A) and hydrochlorothiazide (H), with each of the same components dual combinations in patients with moderate to severe hypertension. 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, estimating the long-term survival and quality-adjusted life-years (QALYs) saved. Costs and outcomes were evaluated over lifetime, divided into annual cycles and discounted at 3.0 % with 2013 as reference year. The analysis was conducted by the Greek third-party-payer perspective. The triple combination treatment cost was estimated at €16,525 compared to €15,480 for V/A, €14,125 for V/H and €11,690 for A/H. The QALYs saved with the triple combination were 12.76 vs. 12.64, 12.61 and 12.38 for double combinations respectively. The incremental cost-effectiveness ratio of the triple combination versus V/A and A/H was far lower than the Greek GDP per capita (€8,690/QALY and €12,695/QALY, respectively) and really close for V/H (€16,192/QALY), suggesting V/A/H combination to be cost-effective. Extensive sensitivity analyses confirmed the robustness of the results. The probability that the triple combination is cost effective was more than 90 % at a willingness-to-pay threshold of €18,000/QALY. This is the first study to evaluate the cost-utility of a single-pill triple combination. The single-pill V/A/H therapy is a cost-effective antihypertensive choice for the treatment of moderate to severe hypertension, compared to its dual components.