Diabetes may be complicated by the development of a symmetrical length-dependent polyneuropathy. In addition to sensory symptoms, patients with diabetic neuropathy (DN) may complain of motor symptoms including weakness and fatigue. The present study was undertaken to evaluate the role of Na+/K+ pump dysfunction in the development of motor symptoms in DN. Nerve excitability techniques, which provide information about membrane potential and axonal ion channel function, were undertaken in 15 patients with established DN, 10 patients with diabetes who had no evidence of neuropathy (DWN) and 15 healthy controls. Excitability parameters were recorded at baseline, and then before and after one minute of maximal voluntary contraction (MVC) of abductor pollicis brevis. Compared to controls, baseline CMAP amplitude was significantly decreased in DN patients with associated reductions in Na+ channel parameters. Following MVC for one minute, there was an increase in normalized threshold in all diabetic patients and controls, consistent with axonal hyperpolarization. When compared to DWN patients and controls, the increase in threshold following MVC was significantly less in DN patients (P<0.05). DN patients with significant baseline reductions in Na+ channel dependent parameters, developed activity-dependent conduction block following MVC. The reduced threshold change and post-contraction reductions in CMAP amplitude are likely to be secondary to Na+/ K+ pump dysfunction. Alteration in Na+/ K+ pump function, coupled with reductions in nodal Na+ currents, may be sufficient to trigger conduction failure in DN patients and are likely to contribute to the clinical symptoms of weakness and fatigue in this condition.