Compound action potentials and electrotonic responses to 150 ms current pulses were recorded from isolated nerve fascicles of human sural nerve biopsies. Compound action potentials in normal bathing solution were characterized by previously described A beta, A delta and C fibre components. In addition, tetrodotoxin-resistant sodium- or calcium-dependent potential components were found when a mixture of tetrodotoxin and the potassium channel blockers 4-aminopyridine and tetraethylammonium was added to the bathing solution. In contrast to tetrodotoxin-sensitive action potentials, tetrodotoxin-resistant sodium- or calcium-dependent potentials could be recorded in the presence of high extracellular potassium concentrations (10-20 mM). Calcium action potentials were found to be sensitive to specific pharmacological antagonists or agonists of L-, N- and P-type calcium channels. Lidocaine, cadmium, verapamil and capsaicin showed unspecific blocking effects on calcium and tetrodotoxin-resistant potentials. Tetrodotoxin-resistant action potentials seem to originate from unmyelinated C fibres since a clear correlation was found between the number of C fibres and the amplitude of tetrodotoxin-resistant calcium and sodium spikes in preparations with different axon type composition. The evidence for tetrodotoxin-resistant Na+ and Ca2+ spikes in peripheral human axons offers new possibilities for a better understanding and/or treatment of abnormalities in the excitability of damaged or diseased peripheral nerves.