Objective: Fibromyalgia is a prevalent disorder characterized by chronic widespread pain and complex symptoms. This study was conducted to investigate the potential therapeutic effect of low-dose irradiation (LDI) alone or in combination with duloxetine on the reserpine-induced fibromyalgia in rats.Methods: Fibromyalgia was induced by administration of reserpine (1mg/kg/s.c) for 3 consecutive days. Duloxetine (30mg/kg, p.o) was administered 60min before a forced swimming test (FST), and rats were exposed to a single dose of -radiation (0.5Gy) 1day before the FST.Results: Reserpine significantly increased immobility time in the FST, decreased the amount of 5-hydroxytryptamine, dopamine, and norepinephrine in cerebral cortex. It also increased malondialdehyde and nitric oxide and reduced glutathione contents in brain tissue. LDI alone or combined with duloxetine completely antagonized reserpine-induced fibromyalgia as assessed by the measured parameters. One of the most significant findings in this study was that the therapeutic effect of duloxetine was more pronounced by its combination with LDI. A possible mechanism of action of LDI and duloxetine responsible for their therapeutic effect was discussed.Conclusion: On the basis of the presented evidences, it could be concluded that LDI alone or combined with duloxetine could be of value in the management of fibromyalgia.