The inflammatory component of peripheral nerve injury may affect the development of local neuropathologic changes as well as the onset of hyperalgesia, the characteristic features of experimental neuropathic pain states. The goal of this study was to determine whether local sciatic injection of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha could reproduce the nociceptive behaviors and endoneurial pathology found following experimental nerve injuries. TNF injection caused significant thermal hyperalgesia and mechanical allodynia for 3 days post-injection in association with nerve edema, splitting of myelin lamellae with vacuolization, Schwann cell injury, fibroblast and macrophage activation, and phagocytosis of lipid debris. The data show that subperineurial injection of TNF proximal to peripheral sensory receptors generates the transient display of behaviors and endoneurial pathologies found in experimental painful nerve injury, and implicates local TNF in the pathologies of neuropathic pain.