Oxidative stress contributes to the vascular and neurological complications of diabetes mellitus. The aim was to evaluate the effects of treatment with the radical scavenger and transition metal chelator, α-lipoic acid, on endothelium-dependent relaxation of the mesenteric vasculature and on superior cervical ganglion blood flow in 8 week streptozotocin-induced diabetic rats. α-Lipoic acid effects on small nerve fiber-mediated nociception were also monitored. For the in vitro phenylephrine-precontracted mesenteric vascular bed, diabetes caused a 31% deficit in maximum endothelium-dependent relaxation to acetylcholine, and a 4-fold reduction in sensitivity. α-Lipoic acid gave 85% protection against these defects. Acetylcholine responses are mediated by nitric oxide and endothelium-derived hyperpolarizing factor: isolation of the latter by nitric oxide synthase blockade revealed a 74% diabetic deficit that was halved by α-lipoic acid. Superior cervical ganglion blood flow, 52% reduced by diabetes, was dose-dependently restored by α-lipoic acid (ED₅₀, 44 mg/kg/d). Diabetic rats exhibited mechanical and thermal hyperalgesia, which were abolished by α-lipoic acid treatment. Thus, diabetes impairs nitric oxide and endothelium-derived hyperpolarizing factor-mediated vasodilation. This contributes to reduced neural perfusion, and may be responsible for altered nociceptive function. The effect of α-lipoic acid strongly implicates oxidative stress in these events and suggests a potential therapeutic approach.