INTRODUCTION: Data on the effects of melatonin administration on metabolic parameters in patients with diabetic nephropathy (DN) is limited and controversial. This study was performed to analyze the effects of melatonin administration on metabolic status in patients with DN. METHODS: This randomized, double blind, placebo-controlled clinical trial was performed on 60 patients with DN. Patients were randomly assigned into two groups to take either 10 mg/d of melatonin (n = 30) or placebo (n = 30) for 12 weeks. Fasting blood samples were taken at baseline and 12 weeks after intervention to quantify metabolic parameters. RESULTS: Melatonin administration significantly reduced plasma fasting glucose (β = -10.64 mg/dL; 95% CI: -20.37 to -0.90; P < .05), insulin (β = -2.37 μIU/mL, 95% CI: -3.33 to -1.41; P < .001), insulin resistance (β = -0.67, 95% CI: -0.98 to -0.35; P < .001), significantly increased insulin sensitivity (β = 0.01, 95% CI: 0.006 to 0.01; P < .05), and plasma HDL-cholesterol levels (β = 2.75 mg/dL, 95% CI: 0.75 to 4.75; P < .05) when compared with the placebo. Melatonin also caused a significant increase in total antioxidant capacity (TAC) (β = 140.45 mmol/L; 95% CI: 80.48 to 200.41; P < .001), and glutathione (GSH) levels (β = 50.36 μmol/L, 95% CI: 94.08 to 0.02; P < .05) when compared with placebo. Ultimately, melatonin could upregulate gene expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) (P < .05) in comparison with placebo. CONCLUSION: Results of this study indicated that melatonin administration for 12 weeks in DN patients had beneficial effects on glycemic control, HDL-cholesterol, TAC and GSH levels, and gene expression of PPAR-γ, but did not affect other metabolic parameters.