SUMMARY1. A three-electrode voltage-clamp method was used to investigate the inactivation of Tl currents through the inward rectifier of frog sartorius muscle fibres, and the interaction between the permeant ions Tl+ and K+.2. In 80 mM-Tl Ringer inward currents inactivated on hyperpolarization along an exponential time course, with time constants that initially increased and then fell with increasing hyperpolarization.3. Because ofthe inactivation process steady-state conductances were smaller than instantaneous conductances at all potentials in Tl Ringer. The steady-state conductance increased to a maximum value at around -100 mV in 80 mM-Tl Ringer, and then fell with increasing hyperpolarization. In K Ringer the steady-state conductance was greater at all potentials than the instantaneous conductance because K currents activate (rather than inactivate) on hyperpolarization.4. Time constants of TI inactivation were the same when measured from the decay of current during a single pulse, or from the rate of recovery from inactivation using either a two-or a three-pulse method, indicating that inactivation obeys first-order kinetics.5. In 80 mM-Tl Ringer steady-state inactivation increased with increasing hyperpolarization, e-fold every 48 mV. This would be consistent with the site at which inactivation occurs experiencing 0.5 of the membrane voltage field.6. Tl+ was more permeant than K+ through the inward rectifier, the permeability ratio PT1+/PK+ being 1-66.7. In solutions containing both T1+ and K+ the membrane showed an anomalous mole-fraction dependence of conductance, the resting potential being more negative, and both instantaneous and steady-state conductances smaller than those recorded in solutions containing only Tl+ or only K+. 8. The reduction in the amplitude of the instantaneous conductance in Tl-K mixtures was voltage-dependent, the block being initially increased and then falling with increasing hyperpolarization.9. Inward currents also inactivated on hyperpolarization in T1-K mixtures. The time constants of inactivation, and the extent of inactivation which occurred, became less dependent on membrane potential in these solutions. * Present address: University Laboratory of Physiology, Parks Road, Oxford OX1 3PT.F. M. ASHCROFT AND P. R. STANFIELD 10. When K+ is the major permeant ion in solution, Tl+ has a blocking effect on the currents carried by K+, and the degree of block is voltage-dependent. Increasing [Tl]. increased the block at all potentials.11. The results of our experiments in solutions containing both Tl+ and K+ are discussed in terms of an interaction between these ions within the channel.