It is unknown whether the use of diuretics is optimal over other antihypertensive agents in patients with chronic kidney disease (CKD) whose blood pressure remains uncontrolled despite treatment with renin-angiotensin system (RAS) inhibitors. In this study, we assessed the additive effects of hydrochlorothiazide (HCTZ) on reducing proteinuria in CKD patients under treatment with losartan (LS). We conducted a multicenter, open-labeled, randomized trial. One hundred and two CKD patients with hypertension and overt proteinuria were recruited from nine centers and randomly assigned to receive either LS (50 mg, n=51) or a combination of LS (50 mg per day) and HCTZ (12.5 mg per day) (LS/HCTZ, n=51). The primary outcome was a decrease in the urinary protein-to-creatinine ratio (UPCR). The target blood pressure was <130/80 mm Hg, and antihypertensive agents (other than RAS inhibitors and diuretics) were added if the target was not attained. Baseline characteristics of the two groups were similar. After 12 months of treatment, decreases in the UPCR were significantly greater in the LS/HCTZ group than in the LS group. There were no significant differences in blood pressure or the estimated glomerular filtration rate between the two groups. LS/HCTZ led to a greater reduction in proteinuria than treatment with LS, even though blood pressure in the LS group was similar to that in the LS/HCTZ group following the administration of additive antihypertensive agents throughout the observation period. This finding suggests that LS/HCTZ exerts renoprotective effects through a mechanism independent of blood pressure reduction.