The role of histamine in the hemodynamic and plasma catecholamine responses to intravenous morphine in subjects without cardiovascular disease and not receiving prior medication has not been reported. Systemic hemodynamics and serum histamine and plasma catecholamine concentrations were measured in 10 subjects before and 2, 5, 10, and 20 min after, 0.3 mg kg-1 IV morphine. Serum histamine concentration increased 2, 5, and 10 min after the morphine. Systolic and mean arterial pressures and systemic vascular resistance decreased and cardiac output increased because of increases in heart rate and stroke volume. The most important changes in hemodynamic function occurred after 2 min in association with a 400% increase in serum histamine concentration; these variables, together with serum histamine concentration, returned toward baseline values after 20 min. There was a negative correlation between peak increase in serum histamine concentration and maximum decrease in systemic vascular resistance. Plasma epinephrine concentrations were elevated 5, 10, and 20 min after morphine injection, suggesting activation of the adrenal medulla by histamine. Our data suggest that histamine plays an important role in the acute hemodynamic and plasma epinephrine response to morphine.