We have recently shown that mineralocorticoid receptor blockade may represent optimal therapy for patients with early diabetic nephropathy who show aldosterone breakthrough during angiotensin-converting enzyme (ACE) inhibitor treatment, and who no longer show the maximal antiproteinuric effects of ACE inhibition. In this study, we explored the effects of the mineralocorticoid receptor antagonist spironolactone on urinary protein excretion in patients with chronic renal disease with proteinuria persistently more than 0.5 g/d, despite maintained blood pressure (BP) control, and including the use of an ACE inhibitor (trandolapril) for at least 10 months. After a 12-week study period of spironolactone treatment (25 mg/d), BP did not change but urinary protein excretion was significantly reduced. The extent of the reduction was on average significantly greater in diabetic patients than in nondiabetics. In patients with diabetic nephropathy, although urinary type IV collagen did not decrease after conventional treatment, it was significantly reduced by spironolactone. None of the patients developed serious hyperkalemia, and no other adverse events were observed. All patients in this study had relatively well preserved renal function. In conclusion, the present study demonstrates that in patients with chronic renal disease with proteinuria persistently more than 0.5 g/d, despite BP control and the use of an ACE inhibitor, adding spironolactone to the conventional treatment produces beneficial effects on urinary protein excretion, particularly in patients with diabetes. Our study suggests that attenuation of mineralocorticoid receptor-mediated effects may become a new goal for patients who escape the antiproteinuric effects of the conventional treatment. Additional, larger, prospective, randomized double-blind studies will be needed for general acceptance of this strategy. Am J Hypertens 2005; 18:44–49 © 2005 American Journal of Hypertension, Ltd.