OBJECTIVE: This study evaluated the effects of melatonin supplementation on parameters of mental health, glycemic control, markers of cardiometabolic risk, and oxidative stress in diabetic hemodialysis (HD) patients. DESIGN: A randomized, double-blind, placebo-controlled clinical trial was conducted in 60 diabetic HD patients, 18-80 years of age. Participants were randomly divided into 2 groups to take either melatonin (2 x 5mg/day) (n = 30) or placebo (n = 30) 1 hour before bedtime for 12 weeks. The effects of melatonin on mental health, metabolic status, and gene expression related to metabolic status were assessed using multiple linear regression adjusting for age and BMI. RESULTS: Melatonin supplementation significantly decreased Pittsburgh Sleep Quality Index (P = .007), Beck Depression Inventory index (P = .001), and Beck Anxiety Inventory index (P = .01) compared with the placebo. Additionally, melatonin administration significantly reduced fasting plasma glucose (β = -21.77 mg/dL, 95% CI -33.22 to -10.33, P < .001), serum insulin levels (β = -1.89 μIU/mL, 95% CI -3.34 to -0.45, P = .01), and homeostasis model of assessment-insulin resistance (β = -1.45, 95% CI -2.10 to -0.80, P < .001), and significantly increased the quantitative insulin sensitivity check index (β = 0.01, 95% CI 0.007-0.02, P < .001) compared with placebo treated subjects. In addition, melatonin administration resulted in a significant reduction in serum high sensitivity C-reactive protein (β = -1.92 mg/L, 95% CI -3.02 to -0.83, P = .001) and plasma malondialdehyde (β = -0.21 μmol/L, 95% CI -0.36 to -0.06, P = .005); also, significant rises in plasma total antioxidant capacity (β = 253.87 mmol/L, 95% CI 189.18-318.56, P < .001) and nitric oxide levels (β = 2.99 μmol/L, 95% CI 0.71-5.28, P = .01) were observed compared with the placebo. CONCLUSION: Overall, melatonin supplementation for 12 weeks to diabetic HD patients had beneficial effects on mental health, glycemic control, inflammatory markers, and oxidative stress.