Evidence for the presence of specific histamine H1- and H2-receptors in the gastrointestinal circulation was obtained using histamine, 2-methylhistamine (a specific H1-agonist), 4-methylhistamine (a specific H2-agonist), and selective H1- and H2-receptor antagonists in the anesthetized dog. Histamine and 2-methylhistamine increased conductance in the vascular beds of the superior mesenteric artery, the left gastric artery and the common hepatic artery, whereas 4-methylhistamine mainly enhanced conductance in the vascular beds of the left gastric artery and the common hepatic artery. All three agents depressed systemic arterial blood pressure. The vasodilatory effect of histamine and 2-methylhistamine on the superior mesenteric artery bed occurred earlier and was of shorter duration than their effect on the two other vessels. The H1-receptor antagonists mepyramine and clemastine blocked the response of the superior mesenteric artery bed to histamine, but had a lesser inhibitory effect on the histamine response of the common hepatic artery and the left gastric artery. The addition of the H2-receptor antagonist cimetidine to mepyramine blockade augmented the inhibiting effect of mepyramine on the common hepatic artery. Cimetidine bolus injections prevented enhancement of vascular conductance by 4-methylhistamine, but did not influence conductance enhancement by histamine or 2-methylhistamine. These data demonstrate there are separable histamine H1- and H2-receptors in the gastrointestinal circulation which are distinguished by anatomic location, temporal relationships of receptor response, and response to specific histamine H1- and H2-agonists and antagonists.