The role of histamine in the cardiovascular responses to hypoxia has not been resolved. Oxatomide, an orally active anti-allergic drug, has been reported to inhibit mast cell discharge and to antagonize any histamine which is released. This drug was administered to six dogs to determine the effect of inhibiting histamine release on the pulmonary vascular and cardiac responses to hypoxia. Oxatomide potentiated hypoxic pulmonary vasoconstriction, but reduced the cardiac output and stroke volume responses to hypoxia. These findings suggest that histamine is released during hypoxia and acts to oppose hypoxic vasoconstriction. In addition, histamine released from peripheral tissues may play an important role in mediating the increased cardiac output observed during acute hypoxia. By utilizing infusions of histamine, oxatomide was also found to be a histamine H1-receptor antagonist.