The effects of cocaine on Na channel of the isolated toad skin were studied. (1) Cocaine applied to the external side of the skin diminished its potential difference and short circuit current and increased its resistance to inward current. The effects were inversely related to the external sodium concentration. A Michaelis–Menten analysis showed a competitive antagonism between cocaine and sodium. (2) Cocaine applied to the external side prevented the appearance of the repetitive activity induced by an inward current pulse. When the concentrations of cocaine necessary to prevent the appearance of repetitive activity were studied at different calcium concentrations, a calcium–cocaine antagonism was found, which was also demonstrated in voltage clamp experiments.