Cigarette smoking is a recognized risk factor for esophageal mucosal disease. For this reason we investigated the effects of smoke on esophageal epithelial electrolyte transport and barrier function in the rabbit. Studies were performed using an extract of cigarette smoke (EOCS) prepared from high-tar, high-nicotine cigarettes. Epithelia were exposed to EOCS in vivo or in vitro in the Ussing chamber. Acute in vivo exposure to EOCS lowered in vivo esophageal potential difference by 61%, and in vitro studies established that this was due to inhibition of active Na transport from mucosa to serosa. Exposure to an EOCS had no effect on net Cl transport or epithelial permeability, the latter reflected by the absence of change in electrical resistance or mannitol flux. The ability of an EOCS to lower potential difference (and inhibit Na transport) was dose-related and equally effective whether contact occurred with the luminal or serosal surface of the tissue. Similar studies performed with an EOCS prepared from filtered smoke established that the component(s) in EOCS responsible for the effects on transport resided in the particulate phase of smoke (i.e., nicotine and "tars"). However, nicotine only inhibited Na transport from the serosal side of the tissue, thus indicating that one or more tars either cause or contribute to the effect of an EOCS on transport. The inhibition by smoke of ion transport in esophageal epithelium may well be an early deleterious link in the pathophysiological chain between cigarette smoking and esophageal mucosal disease.