Peripheral neuropathy is one of the most frequent and severe complications of diabetes. Hydroxytyrosol (HT), the major antioxidant polyphenolic compound of olive oil, has been investigated as a new potential treatment to counteract the progression of peripheral diabetic neuropathy in rats. An established model of streptozotocin-induced diabetes has been used. After confirmation of hyperglycemia, diabetic and nondiabetic animals were randomized to receive either a low dose or a high dose of HT, or the corresponding vehicle, for 6 weeks. At the end of the 6-week period of treatment, HT blunted plasma thiobarbituric acid-reactive substances increase (p < 0.05) and significantly reduced nerve conduction velocity (p < 0.05) and thermal nociception impairment in diabetic rats (p < 0.05). Sciatic nerve Na(+), K(+)-ATPase activity reduction was also abolished by HT (p < 0.05). The present study provides evidence of the therapeutic potential of the natural substance hydroxytyrosol in the early stage of diabetic neuropathy.