Experiments utilizing internally perfused squid giant axons have been carried out to determine the mode of action of tricaine (MS-222) in producing its anesthetic effects. Tricaine, in concentrations of 1 and 3 mM, was applied to the internal surface of the membrane via the perfusion system. Peak sodium current and steady-state potassium current were measured by the axial-wire voltage clamp technique. Tricaine suppressed both of these membrane ionic currents with the major effect being on the peak sodium current. Its action on nerve membrane appeared quite similar to other local anesthetics. One major difference was noted in that tricaine shifts sodium conductance curves in the direction of depolarization along the potential axis, an effect quite similar to that observed with increasing external Ca2+ concentration and with application of pentobarbital.