Our study aimed to explore changes in health-related quality of life (HRQoL) during blood pressure control and blood lipid-lowering therapies. We conducted a 2 × 2 factorial-designed randomized controlled trial in 180 clinical centers in China. At baseline, participants were randomly assigned to an amlodipine + amiloride/hydrochlorothiazide group or an amlodipine + telmisartan group for the blood pressure control treatment and to a statin group or a routine intervention group for the blood lipid-lowering treatment. The allocation ratio was 1:1 for both treatments. Follow-up lasted for 4 years. HRQoL was assessed using the EuroQol five dimensions three levels (EQ-5D-3L) questionnaire every year. Of 13,542 hypertensive patients enrolled in the clinical trial, 9885 were eligible for the analysis. The problems for all dimensions of the EQ-5D-3L descriptive system were slight at baseline and were well preserved in the follow-up period. The EuroQol visual analog scale (EQ VAS) score and the EQ-5D-3L index improved over time (Ptrend < 0.001), with improvements similar among interventions but different between patients who reached the treatment targets or not. Decreases in systolic/diastolic blood pressure and low-density lipoprotein cholesterol and increases in high-density lipoprotein cholesterol were independently correlated with increases in the EQ VAS score and the EQ-5D-3L index. In conclusion, HRQoL is associated with blood pressure/lipid levels but not with specific antihypertensive or lipid-lowering interventions. Blood pressure control and blood lipid-lowering therapies should not be denied to Chinese patients in consideration of their negative effects on quality of life. © 2019, The Japanese Society of Hypertension.