Basophils and mast cells release histamine in hyperosmolar environments. Osmotic release differs significantly from IgE-dependent activation and may be important in the pathophysiology of anaphylactoid reactions during intravenous infusions of hyperosmolar radiocontrast dyes and of obstructive attacks suffered by asthmatics after exercise. To confirm reported differences in osmotic activation of basophils and lung mast cells, the process was compared systematically in the 2 cell types. Both cells were activated by hyperosmolar mannitol, glucose, sucrose, and NaCl, but histamine release from basophils rose sharply to a maximum at 1,050 mOsm/kg, whereas mast cells released maximally at 700 to 750 mOsm/kg. Release was partially Ca2+-dependent in basophils but was highly Ca2+-dependent in mast cells. Release in mast cells was rapid and essentially complete by 5 min, whereas 45 to 60 min were required in basophils. The temperature optimum in both cell types was 32 degrees C, and release in both was enhanced by drugs that increase intracellular cAMP (PGE2, IBMX, and db cAMP). We conclude that osmotic activation of basophils and mast cells is a nontoxic process that differs significantly from IgE-dependent histamine release. If it does indeed participate in the pathophysiology of human disease, different treatment strategies will be required to modulate this contribution.