I ntravenous histamine causes high amplitude repetitive phasic contractions of the in vivo cat pylorus but has little effect on the antrum and duodenum. The genesis of this phasic response was studied using a pinned perfused catheter with openings at the pylorus, antrum, and duodenum. 2-Pyridylethylamine, an H1 agonist, produced phasic contractions similar to histamine whereas dimaprit, an H2 agonist, did not. Conversely, histamine-induced excitation is competitively antagonized by the H1 inhibitor diphenhydramine but not by the H2 inhibitor cimetidine. Thus histamine excitation is mediated through H1 receptor stimulation. Tetrodotoxin caused inhibition of the histamine response indicating that pyloric excitation is partly mediated through a neural pathway. To identify the nature of this pathway adrenergic and cholinergic blockers were used. Atropine, hexamethonium, and propranolol had no effect on the histamine response. Phentolamine and reserpine increased the magnitude of the histamine response. Conversely, phenylephrine blocked the histamine response. We conclude: histamine induces high phasic contractions in the pylorus; this effect is mediated through neural (nonadrenergic noncholinergic) and myogenic H1 receptors; alpha adrenergic stimulation inhibits the histamine response and alpha adrenergic blockade and catecholamine depletion increase it.