In rats trained to discriminate nicotine from saline, a single intraventricular injection of a small dose of the quaternary ganglion-blocking drug chlorisondamine blocked the response to nicotine for four weeks. pentolinium was only weakly active and hexamethonium was inactive as a nicotine antagonist under the conditions used, even in doses that were just below those producing myoclonic jerks. Chlorisondamine had no blocking effect in rats trained to discriminate the non-nicotinic drugs midazolam or morphine from saline. Intraventricular injections of chlorisondamine have a specific and unusually persistent nicotine-blocking action, the mechanism of which requires further investigation.