Background and purpose: Cisplatin-induced nephrotoxicity (CisIN) remains the most dose-limiting adverse effect of its clinical use. The protective effects of melatonin on CisIN have been addressed in several non- clinical and animal studies. This study aimed at investigating the potential effects of melatonin on the prevention of CisIN in human. Experimental approach: Our study was a randomized controlled clinical trial, performed on 66 eligible patients in two groups of melatonin or control (no intervention). Melatonin was administrated daily at a dose of 20 mg for 5 days to the patients receiving cisplatin-containing regimens along with the standard protocol of CisIN prevention. Patient demographic information, blood and urinary indices of nitrogen, creatinine, and electrolytes such as sodium, potassium, magnesium as well as neutrophil gelatinase-associated lipocalin were measured in both groups at the baseline, 24 h and five days after melatonin administration. Findings/Results: Cisplatin administration resulted in significant magnesium and potassium loss in patients with cancer. In comparison with the control group, the prevalence of acute renal injury and the rate of urinary magnesium and potassium loss improved with melatonin administration; however, the results were not statistically significant. Tolerable side effects such as daytime drowsiness, nausea, and vomiting were reported in the melatonin group. Conclusion and implications: Although pretreatment with melatonin led to amelioration in urinary electrolyte loss due to CisIN, it failed to show a positive result on acute renal injury prevention. Future well-designed studies with a longer duration of follow-up, larger sample sizes, and higher doses of melatonin are warranted.