The possibility that norepinephrine (NE) influences lymphoid cell outflow independently of its vasoconstrictor action was investigated in the perfused rat spleen. Using agents that affect the vasoconstrictor tonus of the spleen, we observed an inverse correlation between flow resistance and splenic cell output. The curve obtained served as a reference for evaluating effects of different treatments on the number of cells that are mobilized at defined levels of flow resistance. Perfusion of the beta-adrenergic blocker propranolol either alone or in combination with NE lowered splenic leukocyte outflow clearly beyond the number of cells expected at the corresponding flow resistance. No comparable effects were observed when the alpha-adrenergic blocker phentolamine was perfused. When the vasoconstrictor effect of NE was counteracted by papaverine, splenic cell outflow was significantly higher than expected for the level of flow resistance attained. Furthermore, when NE was perfused together with endotoxin, which does not inhibit the vasoconstriction induced by catecholamines, splenic cell mobilization was severalfold higher than expected at increased flow resistance. Propranolol abrogated this effect to a large extent. Furthermore, perfusion of the beta-agonist isoproterenol stimulated lymphoid cell outflow from the spleen despite increased flow resistance. These studies show a dual effect of NE on cell mobilization from the spleen: cell retention by decreasing blood flow and stimulation of cell output by a beta-adrenergically mediated, smooth muscle-independent mechanism.