Abstract: Fibromyalgia syndrome (FMS) is a chronic musculoskeletal disorder characterized by generalized muscular pain accompanied by fatigue and tenderness at specific anatomic sites called tender points. Although preliminary evidence indicates that melatonin may be effective in treating the pain associated with FMS, no definitive evidence supports this claim. This study was designed to evaluate the significance of using different doses of melatonin, alone or in combination with fluoxetine for the management of FMS. A double-blind, placebo-controlled clinical study was performed on 101 patients (95 women and 6 men) who fulfilled the criteria of the American College of Rheumatology (ACR) of FMS. The patients were randomized into four groups: group A (24 patients) treated with 20 mg/day fluoxetine alone; group B (27 patients) treated with melatonin 5 mg alone; group C (27 patients) treated with 20 mg fluoxetine plus 3 mg melatonin; group D (23 patients) treated with 20 mg fluoxetine plus 5 mg melatonin. Both drugs were given once daily in the morning and night time, respectively, for 8 wk. Each patient was clinically evaluated through direct interview with the patients using the Fibromyalgia Impact Questionnaire (FIQ) at zero time and after 8 wk. Using melatonin (3 mg or 5 mg/day) in combination with 20 mg/day fluoxetine resulted in significant reduction in both total and different components of FIQ score compared to the pretreatment values. In conclusion, administration of melatonin, alone or in a combination with fluoxetine, was effective in the treatment of patients with FMS.