OBJECTIVES: To compare the cost-effectiveness of single-pill triple antihypertensive combination therapy vs double-pill triple combination therapy (fixed-dose dual combination plus free drug class) vs three-pill triple combination therapy (free drug combination) by accounting for medication adherence to each treatment regimen in US. METHODS: A decision analytical model was constructed with one year time horizon from the patient’s perspective. Effectiveness was defined as the percentage (%) attainment of target systolic blood pressure (SBP) levels (<140 mm Hg) based on adherence to each treatment strategy. Adherence was defined as having proportion of days covered (PDC)>=80%. The probability of being adherent and achieving target SBP goal based on the adherence were obtained from the published literature. Direct medical cost (annual treatment cost for each strategy) was evaluated based on the adherence levels and adjusted to the year of 2015 by using consumer price index (CPI). The average cost effectiveness ratio (ACER) was calculated as the cost per % attainment of the target SBP level. RESULTS: The ACER for single-pill triple combination therapy was lowest ($1,566.82) followed by two-pill ($1,856.32) and three-pill triple combination therapy ($2,210.42). The annual treatment cost was $964.85, $1133.72 and $1344.12 for single-pill, two-pill and three-pill combination therapy, respectively. The probability of being adherent was 55.3%, 40.40% and 32.60% to single-pill, two-pill and three-pill regimen. The probability of achieving target SBP level was 63.1% for adherent patients and 59.7% for non-adherent patients. CONCLUSIONS: Compared to two-pill and three-pill triple combination therapy, single-pill triple antihypertensive therapy was more cost effective by considering SBP as the effectiveness outcome in the short term. Further analysis accounting for indirect medical costs from the societal perspective and using other outcome measures like quality adjusted life years (QALYs) in the long term needs to be further investigated. KEYWORDS: decision analytical model, cost effectiveness, hypertension, combination therapy.