The action of metiamide, an H2 antagonist, was tested for its effect upon lower esophageal sphincter (LES) function in the anesthetized opossum. Intravenous infusions of metiamide gave a dose-related increase in LES pressure. A maximum increase in pressure of 17 mm Hg was attained at 2.0 mg per kg-hr of metiamide. This dose of metiamide abolished acid secretion in response to gastrin I, but augmented the maximal LES response to this hormone. Studies in vitro showed that metiamide augmented the maximal LES muscle responses to gastrin I or histamine but had no effect on other agonist responses. Metiamide alone did not alter LES muscle tension. An inhibitory response to gastrin I or histamine could be demonstrated in the presence of atropine or diphenhydramine, respectively, on muscle which had first been depolarized with KCl. These inhibitory responses were antagonized by metiamide. These studies indicate that metiamide: (a) increases LES pressure; (b) selectively augments LES muscle excitatory responses to gastrin I or histamine; and (c) selectively antagonizes inhibitory muscle responses to histamine or gastrin I.