Antihypertensive drugs can differ in target organ protection despite similar blood pressure (BP) control. We compared the effects of losartan (L) and chlorthalidone (C) on renal vascular resistance index (RVRI) in 194 grade I to II, non-diabetic hypertensive patients with increased RVRI (>0.68 m/s by echo-Doppler) but normal renal function. Patients were randomly allocated to C 25 mg/d or L 50 mg/d according to a single blind, PROBE study design. After 4 weeks of treatment, 92 patients (48 L/44 C) with BP <140/90 mm Hg were enrolled in the long-term phase of the study. After 12 months a normalization of RVRI was observed in 47 of 48 patients treated with L (97.5%) and only in 14 of 44 of those treated with C (25.8%) despite no differences in BP control. Patients whose RVRI remained elevated during C therapy underwent a 2-week washout period and then were treated with L 50 mg/d for 12 additional months. After that period 28 of 30 (95%) of patients who were nonresponders to C showed a normalization of RVRI despite no differences in BP control. In conclusion, our data suggest that treatment with L can improve renal hemodynamic and exert a protective renal effect beyond BP control in patients with hypertension.