Muscle function is often severely impaired in peripheral arterial disease (PAD), but the effects of repeated ischemic events upon nerve and muscle are incompletely characterized. We performed comprehensive electrophysiologic studies and skeletal muscle histologic analysis in six patients with unilateral PAD and five control subjects matched for age and activity level. In the PAD patients, all ischemic legs showed both electrophysiologic and histologic evidence of chronic partial denervation-reinnervation restricted to distal muscles. Two of the PAD patients had evidence of milder distal denervation in the nonischemic legs. Two of the controls had denervation in at least one leg, but in each case electrophysiologic findings were pathognomonic of L-5 and S-1 radiculopathies. All other control legs and nonischemic legs were normal. These results suggest that recurrent ischemia associated with PAD may cause muscle denervation, which may be one of the mechanisms responsible for decreased exercise performance in these patients.