Background and Aims: According to the clinical guidelines on chronic kidney disease with hypertension, combination therapy with multiple renin-angiotensin-aldosterone system (RAAS) blockers have been recommended as standard first-line therapy. To date, dual and triple blockade of the RAAS has been evaluated. The aim of this study was comparing three (ACEI+ARB+b blocker) and two (ACEI+ARB) directional inhibitions of RAAS in treatment of diabetic nephropathy.Materials and Methods: In an experimental interventional study, 103 diabetic patients without ESRD were recruited in Tabriz Sina Hospital during a one-year period. The patients were randomized in two groups: group A received triple blockade of RAAS with ACEI+ARB+b blocker, and group B received dual blockade with ACEI+ARB (and placebo). Basal and post treatment parameters including blood pressure, urine albumin, serum BUN, Cr, Na, K, HbA1C, and GFR were compared.Results: Both study groups were matched for age, sex and duration of diabetes mellitus. Decrease of blood pressure, albuminuria, BUN, and Cr was more significant in group A compared with group B. The GFR rose more significantly in group A compared with group B. The frequency of hyperkalemia was significantly higher in group A.Conclusion: Triple blockade of RAAS is more efficient that dual blockade in prevention of diabetic nephropathy however, meticulous selection of patients should be considered because of higher risk of hyperkalemia.