A series of preclinical and clinical studies have shown the immunomodulatory effect of  melatonin, especially in the state of chronic inflammation. A double-blind, randomized, parallel-group, placebo-controlled clinical trial was designed to study the tolerability and efficacy of supplemental therapy with melatonin (3 mg/day) in comparison to placebo in relapsing-remitting MS (RRMS) patients receiving once weekly interferon beta. Patients were followed up for 12 months. Primary outcomes consisted of the number of relapses, change in Extended Disability Status Scale (EDSS), and the number and volume of new T2 and gadolinium-enhancing brain lesions. Secondary outcomes included change in performance on Multiple Sclerosis Functional Composite (MSFC) as well as change in fatigue and depression. The outcomes were evaluated every three months. Twenty-six patients (13 in each group) were recruited in the study. All participants, except for one patient in the placebo group, completed the study. No patient reported serious adverse events. There was no significant difference either in primary or secondary outcomes between melatonin and placebo arm. However, a trend for beneficial effect was observed for melatonin on change in MSFC performance and the cognitive subscore of the Modified Fatigue Impact Scale (p=0.05 and 0.006, respectively, not corrected for multiple comparisons). We found no significant effect for treatment with melatonin on measures of clinical and functional disability and development of brain lesions in our small sample-size study. Studies with higher statistical power and longer follow up are needed to further evaluate the potential immunomodulatory effect of melatonin in RRMS treatment.