Hypoglycemia may cause axonal nerve fiber degeneration, but to do so it must be severe (less than 1.5 mmol/L) and of long duration (greater than or equal to 12 hours). Since in our previous study, systemic PO2, PCO2, pH, blood pressure, temperature, and hematocrit were maintained within physiologic limits, fiber degeneration cannot be attributed to systemic hypoxia. In this study the spatial distribution of axonal degeneration was assessed in transverse epoxy sections and teased fibers from different proximal-to-distal levels of nerves of the lower limb of the rats. Reactions in lumbar spinal motor neurons, spinal ganglia, and fasciculus gracilis were also studied. Axonal degeneration was the characteristic fiber alteration and it predominated in central fascicular distributions of distal sciatic, proximal tibial, and proximal peroneal nerves. This proximal-to-distal and central fascicular spatial distribution is not typical of distal polyneuropathy or of neuronal degeneration, but it is characteristic of a focal or multifocal nerve trunk neuropathy. Although local hypoxic-ischemic injury, possibly mediated by enhanced sympathetic tone, has not been excluded, we postulate a generalized deficiency of energy substrate manifesting itself by fiber degeneration at watershed zones of poorest perfusion.