Background: Neuropathic pain is a chronic pain caused by damage to the central nervous system and the peripheral. Caffeine is a non-selective antagonist of A1, A2a, receptors of adenosine, which has a protective effect on neuropathic pain in some doses by inhibiting A2a, A2b receptors. Considering that the nitric oxide (NO) levels are apparently effective in the parts of caffeine central effects, thus, the purpose of this study was to investigate the effect of chronic caffeine administration on the hyperalgesia in neuropathic rats and levels of nitric oxide metabolites (NOx). Materials and Methods: The present study was conducted on 40 adult male rats weighing 220-250 gr. Neuropathic pain was induced by chronic constriction injury (CCI) of sciatic nerve. Animals were randomly divided into 5 groups (n=8). The control group, which did not intervene on the sciatic nerve, the sham group, which the animals were surgically implanted but the sciatic nerve was not tied, the CCI group and test groups received oral doses of caffeine orally (100 and 300 mg/L) for 28 days. Hyperalgesia was measured in all groups with Plantar test on days 4, 7, 14, 21, and 28 after surgery. The levels of NOx were measured by the Griess method in lumbar spinal cord tissue on day 28. Results: Neuropathic rats showed decreased pain thresholds in hyperalgesia. Chronic caffeine at the doses of 100 and 300 mg/L in drinking water for 28 days significantly alleviated hyperalgesia (P<0. 01, P<0. 001). Conclusion: According to the results of this study, chronic intake of caffeine can reduce hyperalgesia in neuropathic rat. It seems that the NO pathway is not involved in the central effect of caffeine on pain threshold in the CCI model of neuropathic pain.