A randomized trial powered to detect a reduced incidence of ESRD or cardiovascular mortality with combined ARB and ACE inhibition as compared to ACE inhibition or ARB alone would require several thousands of patients. However, identifying high risk patients who may benefit the most of nephro- and cardio-protective therapy would allow to design an adequately powered trial with remarkably less patients. By using a Bayesian decision-tree analysis we identified, among patients included in the RENAAL study, a subgroup of high risk patients with a baseline serum creatinine of 1.8 mg/dl or more and spot morning urine albumin to creatinine ratio >1000mg/g or more. Of note, over 3.5 year follow-up, 70% of these high-risk patients progressed to ESRD despite ARB therapy. Thus, the incidence of ESRD was three-fold higher in high-risk patients (20%) than in the whole study group (6.8%). High risk patients with these clinical characteristics are therefore the ideal target for randomized clinical trials aimed to evaluate the effect of novel nephro- and, possibly, cardio-protective treatments in overt nephropathy of type 2 diabetes.