Diabetic peripheral neuropathy (DPN) is one of the most common diabetic chronic complications. The aim of this study was to clarify whether grape seed proanthocyanidins extracts (GSPE) are therapeutic agents against DPN. In this study, we used streptozocin (STZ) to induce diabetic rats. GSPEs (250 mg/kg body weight/d) were administrated to diabetic rats for 24 wk. Motor nerve conductive velocity (MNCV) and mechanical hyperalgesia were determined in the rats. Serum glucose, glycated hemoglobin, advanced glycation end products (AGEs), and tissue malondialdehyde (MDA) and superoxide dismutase (SOD) were determined. Light and electron microscopy were used to observe the changes of nerval ultrastructure.GSPE significantly increased the MNCV, mechanical hyperalgesia and SOD of diabetic rats (p<0.05) and reduced the AGEs and MDA of diabetic rats (p<0.05). After being treated by GSPE, the severe segmental demyelination was decreased and Schwann cells were improved. In conclusion, GSPE plays an important role against DPN. With the decreasing of AGEs and MDA, it can ameliorate oxidation-associated nerval damage. This study may provide a new recognition of natural medicine for the treatment of DPN.