Compound action potentials were recorded from the isolated frog sciatic nerve using either sodium or lithium as the permeant ion, and an assessment of the action of local anaesthetics was made. The compound action potentials evoked from the nerve were not different in terms of their mean amplitude or time to peak whether recorded with sodium or lithium as the permeant ion. The local anaesthetics tested, procaine, lignocaine and benzocaine, were more potent, as measured by their IC50 values, by 2.3, 2.1 and 1.8 times, respectively, when lithium rather than sodium was used as the permeant ion. The sensitivity of the nerves to tetrodotoxin was not significantly different whether sodium or lithium was used as the permeant ion. The slope of the concentration inhibition curves was not significantly altered in the presence of sodium or lithium for any of the compounds tested. These results are consistent with the idea that the binding site for local anaesthetics is intimately associated with the pore region of the channel and that the nature of the permeant ion can alter the interaction of the drugs with the sodium channel. However, since this is not a common feature of all compounds which block sodium channels by interacting at the pore, it may help refine the existing structural models of sodium channels.