Neuropathic diseases typically begin distally and spread proximally. Irrespective of the etiology, pathological investigations often indicate changes consistent with ischemia. In the present study, threshold tracking was used to investigate length-dependent differences in ischemic susceptibility of lower-limb axons in 6 healthy volunteers, with ischemia induced by a sphygmomanometer cuff inflated to 200 mm Hg and maintained for 13 minutes. Following stimulation of the peroneal nerve at the fibula neck, compound muscle action potentials were recorded proximally from tibialis anterior (TA) and distally from extensor digitorum brevis (EDB). During ischemia, excitability changes were consistent with nerve depolarization, with a greater reduction in threshold in EDB than TA. This reduction in threshold was associated with an increase in refractoriness, decrease in superexcitability, and prolongation of strength-duration time constant, consistent with axonal depolarization. With release of ischemia, reversal of these changes was associated with an increase in threshold, greater in EDB than TA, indicating axonal hyperpolarization. The rate of recovery of threshold was similar proximally and distally, arguing against a gradient in Na(+)/K(+) pump function along the peroneal nerve. The greater changes in threshold in EDB during and after ischemia suggest an increased susceptibility of more distal axons to ischemia and are likely to contribute to the length-dependent development of neuropathy.