OBJECTIVES: To describe the relationship between the cost-sharing and antihypertensive medication therapy of fixed-dose combination (FDC) versus mono therapy. METHODS: Cross-sectional study of all individuals surveyed in the U.S. Medical Expenditure Panel Survey 2006 with at least one hypertension diagnosis, only 30 pills antihypertensive drugs per prescription, and either FDC or mono therapy were included. Bivariate and multivariate generalized linear regression models that controlled for demographic, socioeconomic and drug characteristics assessed the association between the costs and therapy type.  Crude and adjusted mean out-of-pocket cost and total payers paid amount were also computed and compared. The 2006 full-year person level sample weight was applied in the statistical analysis. RESULTS: The cohort consist of 2,190 hypertension patients with a mean age of 60.3 years, 55.9% female, with average Charlson index of 0.36(rang 0-8) and 35% population were on FDC therapy. The multivariate model that adjusted for demographic, socioeconomic and drug factors, showed FDC therapy had no significant association with out-of-pocket cost with coefficient(95% confidential interval) of 1.0742(-0.9577 to 3.1061), but was negatively associated with the total cost with coefficient of -6.6614(-10.1180 to -3.2048).  The crude average increase in out-of-pocket and total payer costs per patient with 30 pills per prescription between FDC versus mono therapy were $6.22(95% confidence interval, $4.42 to 8.02) and $5.67($2.66 to 8.67), respectively, while the adjusted average increase in costs were $1.47($-0.29 to 3.23) and $2.00($-1.02 to 5.01), respectively. CONCLUSIONS: The association results suggested that FDC antihypertensive therapy does not affect patient out-of-pocket cost, but FDC therapy reduces payer cost. Considering the number of agents in one pill of the therapy, FDC therapy does not cost significantly more to patient and payer than mono therapy. Our results also provide economic evidence for clinicians to help ease the financial burden from out-of-pocket cost in patients who need two antihypertensive agents therapy.