Background: Tumor necrosis factor-alpha and other proinflammatory cytokines are becoming well recognized as key mediators in the pathogenesis of many types of neuropathic pain. Thalidomide has profound immunomodulatory actions in addition to their originally intended pharmacological actions. There has been debate on the analgesic efficacy of opioids in neuropathic pain. The aim of this study was to investigate the effect of thalidomide and morphine on a spinal nerve ligation model in rats. Methods: Male Sprague-Dawley rats weighing 100-120 g were used. Lumbar (L) 5 and 6 spinal nerve ligations were performed to induce neuropathic pain. For assessment of mechanical allodynia, mechanical stimulus using von Frey filament was applied to the paw to measure withdrawal threshold. The effects of intraperitoneal thalidomide (6.25, 12.5, 25 and 50 mg/kg, respectively) and morphine (3 and 10 mg/kg, respectively) were examined on a withdrawal threshold evoked by spinal nerve ligation. Results: After L5 and 6 spinal nerve ligation, paw withdrawal thresholds on the ipsilateral side were significantly decreased compared with pre-operative baseline and with those in the sham-operated group. Intraperitoneal thalidomide and morphine significantly increased the paw withdrawal threshold compared to controls and produced dose-responsiveness. Conclusions: Systemic thalidomide and morphine have antiallodynic effect on neuropathic pain induced by spinal nerve ligation in rat. These results suggest that morphine and thalidomide may be alternative therapeutic approaches for neuropathic pain.