OBJECTIVES: A secondary objective of a phase-III study spanning 54 weeks was to measure changes in the health-related quality of life (HRQoL) of 2,690 patients ≥18 years of age with moderate-to-severe hypertension who ended up receiving one of six doses of olmesartan/amlodipine/hydrochlorothiazide (OLM/AML/HCTZ) using the MINICHAL and EQ5D instruments. METHODS Descriptive statistics were used to measure blood pressure and HRQoL scores over the study period. Analysis of covariance (ANCOVA) was used to identify those factors (i.e. age, sex etc.) that could possibly have influenced HRQoL.  Linear regression was used to assess the relationship between changes in blood pressure and HRQoL scores. RESULTS At the study start 90.8% of patients had Grade 2 or 3 hypertension, but at the study end 91.9% had normal/high-normal BP.  Patients' baseline MINICHAL mood and somatic domains scores were 5.5 and 2.6. Over the study period HRQoL improved as both MINICHAL scores decreased by 31-33%. Patients' baseline EQ5D index and VAS score was 0.9 and 73.4 respectively, increasing by 6% and 12% over the study period. Patients’ QALY gain over the 54 weeks study period was estimated to be 0.029 QALYs. Linear regression was unable to detect any correlation between the changes in blood pressure and HRQoL scores. The ANCOVA model showed that changes in  patients' HRQoL was likely to have been influenced by patients’ grade of hypertension at baseline, the amount of concomitant medication ("pill burden") and patients' antihypertensive treatment in the last 26 weeks of the study. CONCLUSIONS OLM/AML/HCTZ reduced blood pressure and significantly increased blood pressure control whilst improving patients' HRQoL. Reducing patients' pill burden is likely to increase adherence to treatment and improve blood pressure control. Hence, when prescribing antihypertensive agents physicians should consider the impact that pill burden has on adherence to treatment, achieving blood pressure control and patients' HRQoL.