OBJECTIVES: To analyze the cost-effectiveness of treating hypertensive patients with azilsartan medoxomil and chlorthalidone fixed dose combination (AZL-M/CLD FDC) therapy compared with other angiotensin receptor blocker (ARB) and hydrochlorothiazide (HCT) combinations commonly available in the US market. METHODS: A Markov Cohort Simulation approach was utilized. Simulated patients start in a hypertensive state and are followed over multiple time periods as they transition between mutually exclusive health states. Cost per Quality Adjusted Life Year (Cost/QALY) and Incremental Cost-effectiveness Ratios (ICERs) are calculated over all possible dose combinations. Cardiovascular disease (CVD) risks were based on the Framingham risk equations. FDCs of HCT and eight ARBs commonly used in the US market (Atacand HCT, Avalide, Benicar HCT, Hyzaar, Diovan HCT, generic Losartan HCT, Micardis HCT and Teveten HCT) were included in the analyses. RESULTS: Results suggest that AZL-M/CLD FDC is less expensive and more effective in lowering BP versus all branded ARB/HCT FDC comparators. When considering average costs and the CVD risks based on the Framingham risk equations for all therapies over a five year time horizon, AZL-M/CLD FDC would remain the least expensive and most effective branded ARB/Diuretic FDC therapy up to a 23.5% unit cost increase with the average office SBP reduction of -22.3% and up to 18.1% unit cost increase with the 24-hour ambulatory BP reduction of -17.0%. CONCLUSIONS: AZL-M/CLD FDC is predicted to be less expensive and more effective in reducing blood pressure and cardiovascular risk when compared to all branded ARB/HCT FDC comparators during a five year time horizon.