Voltage clamp experiments were performed in single myelinated nerve fibers of the rat and the effects of phenytoin (PHT) and carbamazepine (CBZ) on the ionic membrane currents were studied. PHT and CBZ are almost selective blockers of Na channels. The main part of this inhibition is a potential-dependent block which can be removed by hyperpolarization. The dose-response curve of PHT was described as a first-order reaction with Kd = 37 microM; 100 microM CBZ was equally as effective 100 microM PHT. Both drugs shift the steady-state Na inactivation curve (h infinity (V] to more negative membrane potentials and decrease its steepness. PHT and CBZ have equimolar effects on the shift and decrease in steepness of h infinity (V). All of the drug-induced effects depend on drug concentration. Both drugs induce a slowing of recovery from Na inactivation. PHT has a stronger slowing effect than CBZ. From this ensues a frequency-dependent block, which is more pronounced in the presence of PHT than of CBZ. The effects of both drugs can be interpreted in the framework of the modulated receptor hypothesis.