Background: Diabetic nephropathy is the most common cause of kidney failure. We investigated the beneficial effects of spironolactone, alone and in combination with hydrochlorothiazide, on diabetic nephropathy. Methods: This randomized clinical trial was conducted on 60 type 2 diabetic patients with nephropathy. The patients were allocated to three groups of 20 to receive spironolactone (50 mg/d) plus placebo, spironolactone (50 mg/d) plus hydrochlorothiazide (25 mg/d), or placebo plus hydrochlorothiazide (25 mg/d). The duration of the study was three months. Measurements of 24-hour urine protein and other markers were performed at start and end of the study. Findings: Of 60 patients, 43 were male. The mean age of patients was 56.8 ± 8.3 years. The three groups were homogeneous regarding general factors. At the end of the study, a significant difference in proteinuria was observed between the groups. In the groups that received spironolactone, the mean 24-hour urine protein was reduced (200 mg/24h). However, there was no significant change in the last group. The mean serum potassium in the first group showed a significant increase (0.26 meq/l). However, there were no significant increases in the second and third groups. Conclusion: This investigation showed that spironolactone plus hydrochlorothiazide had a significant effect on reducing proteinuria without causing hyperkalemia and renal failure in patients with glomerular filtration rate > 50 cc/min. Therefore, spironolactone can serve as a renoprotective drug in diabetic nephropathy