Studies were conducted in anesthetized dogs to assess whether histamine H1- and/or H2-receptors play a role in post-prandial intestinal hyperemia. The vascular and metabolic responses of jejunal segments to intra-arterial infusion of histamine and luminal placement of food before and after administration of tripelennamine, an H1-receptor antagonist, metiamide, an H2-receptor antagonist, and the combination of both antagonists were compared. Administration of the antagonists had no effect of jejunal blood flow and intestinal oxygen uptake (VO2). Tripelennamine or metiamide alone attenuated while the combination of both blocked the histamine-induced increases in blood flow and VO2. Metamide alone had no effect on the food-induced increases in flow and VO2. Tripelennamine significantly attenuated the food-induced increase in flow and blocked the increase in VO2. A 30% increase in flow was reduced to 15% after tripelennamine. The effects of tripelennamine plus metiamide were statistically the same as those of tripelennamine alone. It is concluded that endogenous histamines may play a role in postprandial intestinal hyperemia, and the effect is primarily mediated by the H1-receptors.