Reduction of nephrotic range albuminuria is associated with markedly improved renal and cardiovascular outcome in patients with diabetic nephropathy. Aldosterone has been suggested to play a role in the progression of diabetic nephropathy. We therefore aimed to evaluate the short-term effect of aldosterone antagonism with spironolactone on nephrotic range albuminuria and blood pressure in diabetic nephropathy. Twenty Caucasian patients with diabetic nephropathy and nephrotic range albuminuria (>2500 mg/24 h) despite recommended antihypertensive treatment completed this double-masked, randomized crossover trial. Patients were treated in random order with spironolactone 25 mg once daily and matched placebo for 2 months, on top of ongoing antihypertensive treatment, including an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker in maximally recommended doses. Median (range) number of antihypertensive drugs was 3 (2-5). After each treatment period, albuminuria, 24-h ambulatory blood pressure, and glomerular filtration rate (GFR) were determined. Spironolactone on top of recommended renoprotective treatment induced a 32% (95% confidence interval (CI): 21-42%) reduction in albuminuria from (geometric mean (95% CI)) 3718 (2910-4749) mg/24 h on placebo treatment (P<0.001). There was a significant reduction in 24-h blood pressure of 6 (2-10)/4 (2-6) mm Hg and day blood pressure of 7 (3-12)/5 (3-7) mm Hg (P<0.01), whereas night blood pressure remained unchanged. Spironolactone induced an insignificant reversible reduction in GFR of 3 ml/min/1.73 m2 from 64 (27) ml/min/1.73 m2. No patients were excluded due to adverse events. Our results suggest that spironolactone treatment on top of recommended renoprotective treatment including maximal renin-angiotensin system blockade may offer additional renoprotection in patients with diabetic nephropathy and nephrotic range albuminuria.