The effect of Desferal (desferrioxamine), an iron-chelating agent with allergic side effects, was examined on human basophils and rodent mast cells (MCs) in vitro and in the human skin. Even at a high concentration (100 mg/ml), the drug neither induced histamine release (HR) from human basophils nor primed these cells to release higher amounts of histamine when they were activated with f-met-peptide or anti-IgE antibodies. In contrast, in all seven subjects studied, intradermal injection of Desferal (0.1 mg/ml to 100 mg/ml) elicited classic wheal-and-flare responses. Ingestion of 10 mg of cetirizine, an H1 antagonist, 3 hours before the intracutaneous administration of Desferal, significantly reduced the diameters of both wheal-and-flare reactions, indicating that the drug caused local HR. Desferal also induced HR from rat peritoneal MCs in vitro but had no effect on mouse bone marrow-derived MCs. These results suggest that Desferal has a direct, IgE-independent, stimulatory effect on connective tissue-type MCs. Thus, it may be used as a positive control in skin testing.