In the present study, the authors examined whether treating streptozotocin-induced diabetic rats with the combination of alpha-lipoic acid and fidarestat, an aldose reductase inhibitor, can promote the formation of dihydrolipoic acid in diabetic animals and thereby enhance the efficacy of alpha-lipoic acid as monotherapy toward preventing diabetic vascular and neural dysfunction. Treating diabetic rats with the combination of 0.25% alpha-lipoic acid (in the diet) and fidarestat (3 mg/kg body weight) prevented the diabetes-induced slowing of motor nerve conduction velocity and endoneurial blood flow. This therapy also significantly improved acetylcholine-mediated vasodilation in epineurial arterioles of the sciatic nerve compared to nontreated diabetic rats. Treating diabetic rats with 0.25% alpha-lipoic acid and fidarestat (3 mg/kg body weight) was equally or more effective in preventing vascular and neural dysfunction than was monotherapy of diabetic rats with higher doses of alpha-lipoic acid or fidarestat. Treating diabetic rats with the combination of 0.25% alpha-lipoic acid and fidarestat (3 mg/kg body weight) significantly improved several markers of oxidative stress and increased the serum levels of both alpha-lipoic acid and dihydrolipoic acid. These studies suggest that combination therapy consisting of alpha-lipoic acid and fidarestat may be more efficacious in preventing diabetes-induced vascular and neural dysfunction in peripheral tissue compared to monotherapy, which requires higher doses to be equally effective. The effect of this combination therapy may in part be due to the increased production and/or level of dihydrolipoic acid.