ABSTRACT Background: Diabetic neuropathic pain, an important microvascular complication in diabetes mellitus, is recognized as one of the most difficult types of pain to treat. It is not possible to nominate a single drug as the first-line treatment for diabetic peripheral neuropathic pain. Aim: the present study explored the effects of pioglitazone and/or fluoxetine on tactile allodynia and thermal hyperalgesia in a neuropathic pain with a focus on the role of the proinflammatory cytokines: TNF-α and IL-6. Methods: 60 adult male white albino-rats were randomly assigned into 2 groups non-diabetic and diabetic. Each group subdivided into 5 groups (n=6 rats in each group) and treated for 14 days in diabetic and non-diabetic rats as follow: group 1 fed normal diet and served as normal control group, group 2 fed high cholesterol diet and received no treatment; group 3 fed high cholesterol diet plus pioglitazone; group 4 fed high cholesterol diet plus fluoxetine ; group 5 fed high cholesterol diet plus pioglitazone and fluoxetine. All groups subjected to partial sciatic nerve ligation (PSL) and injected with single intra-peritoneal injection of streptozotocin except normal group. Results: administration of pioglitazone and/or fluoxetine attenuated the tactile allodynia and thermal hyperalgesia produced by peripheral sciatic nerve ligation in non-diabetic and diabetic rats which confirmed by histopathological examination. On the other hand, fluoxetine failed to ameloriate tactile allodynia and thermal hyperalgesia in diabetic groups. The effect of pioglitazone and fluoxetine were accompanied with significant decrease in peripheral sciatic nerve tissue expression of proinflammatory cytokines TNF-α and IL-6. Conclusion: these results suggested that pioglitazone and fluoxetine can alleviate neuropathic pain through attenuation of proinflammatory cytokine upregulation in both diabetic and non diabetic rat.