Several esophageal pathologies are associated with an increase number of mast cells in the esophageal wall. We addressed the hypothesis that activation of esophageal mast cells leads to an increase in the excitability of nearby sensory C-fibers. Guinea pigs were actively sensitized to ovalbumin. The mast cells in the esophagus were selectively activated ex-vivo by superfusion with ovalbumin. Action potential discharge in guinea pig vagal nodose esopahgeal C-fiber nerve endings was monitored in the isolated (ex vivo) vagally-innervated esophagus using an extracellular recordings. Ovalbumin activated esophageal mast cells leading to the rapid release of about 20% of the tissue histamine stores. This was associated with a consistent and significant increase in excitability of the nodose C-fibers as reflected in a 2-3 fold increase in action potential discharge evoked by either mechanical (increases in intralumenal pressure) or chemical (, -methylene ATP) stimulation. The increase in excitability persisted unchanged for at least 90 minutes after ovalbumin was washed from the tissue. This effect could be prevented by the histamine H1 receptor antagonist pyrilamine, but once the increase in excitability occurred, it persisted in the nominal absence of histamine and could not be reversed even with large concentrations of the histamine receptor antagonist. Activation of esophageal mast cells leads to a pronounced and long-lived increase in nociceptive C-fiber excitability such that any sensation or reflex evoked via the vagal nociceptors will likely be enhanced. The effect is initiated by histamine via H1 receptor activation, and maintained in the absence of the initiating stimulus.