The present study is to investigate whether spironolactone is better than hydrochlorothiazide (HCTZ) for blood pressure (BP) control and arterial stiffness improvement. Five-hundred-sixty-six uncontrolled hypertensive patients with 2 different classes of antihypertensive medications treatment were enrolled. Spironolactone or HCTZ was randomly prescribed for 4 weeks. Carotid-femoral pulse wave velocity (cf-PWV) was measured at baseline and after 4 weeks’ of spironolactone or HCTZ treatment. Between-group differences were evaluated, and logistic regression analysis was performed to evaluate the association of cf-PWV increase and incident resistant hypertension. No significant differences in baseline characteristics were observed between spironolactone and HCTZ groups. After 4 weeks’ treatment, both systolic BP and cf-PWV were reduced more profoundly in spironolactone group versus HCTZ group (P < .05). Pearson and Spearman correlation analysis showed that age, diabetes mellitus, and HCTZ were positively correlated with cf-PWV, while spironolactone was negatively with cf-PWV. Logistic regression analysis indicated that per 1-standard deviation increase in cf-PWV was associated with 92% higher incidence of resistant hypertension. After adjusted for spironolactone, no significant association between cf-PWV increase and incident resistant hypertension was observed, indicating that the adverse effect of arterial stiffness on resistant hypertension development might be reversed by spironolactone treatment. In summary, uncontrolled hypertensive patients with spironolactone treatment appear to have better BP control and arterial stiffness improvement.