To evaluate the role of the Nrf-2/HO-1 pathway in neuropathic pain in diabetic rats. Methods: Twenty-four male Sprague-Dawley rats were randomly divided into 3 groups (n=8 per group): normal group (group C), diabetes group (group D), and diabetes+tBHQ group (group DT). Diabetes was induced in rats by intraperitoneal injection of 1% streptozotocin at 60 mg/kg. After successfully establishing diabetes model, group DT was given tBHQ at 30 mg/kg from day 3 until day 42. Mechanical withdrawal threshold (MWT) and motor nerve conduction velocity (MNCV) were evaluated at 2, 4, and 6 weeks. After 6 weeks, rats were sacrificed and spinal cords were removed for determination of pathology change by Nissl staining; pathology change of the sural nerve was evaluated by electron microscopy (EM); Nrf-2 and HO-1 were detected by western blot. Results: Compared with group C, damage to spinal structure was significantly decreased, MWT and MNCV were significantly decreased, and Nrf-2 and HO-1 expression was down-regulated in group D (all P< 0.05). Compared with group D, spinal structure damage was minor, MWT and MNCV were increased, and Nrf-2 and HO-1 expression was up-regulated in group DT (all P<0.05). Conclusion: The Nrf-2/HO-1 pathway may be involved in the regulation of diabetic neuropathic pain.