BACKGROUND Sera of about 30% of patients with chronic idiopathic urticaria (CIU) have increased histamine releasing activity (HRA+) on normal basophils. It is not known whether other CIU sera would be HRA+ if a more sensitive histamine release assay was used. Although most HRA+ CIU sera appear to have anti Fc(epsilon)R1 activity, it is not known whether post-binding basophil intracellular events are similar to those after anti-IgE stimulation. RESULTS In the presence of D2O, the HR stimulated by 28 previously documented HRA- sera increased from 4+/-0.4 to 21+/-4% with 13 of the 28 sera now considered HRA+. No previous HRA sera was HRA+ with IL-3 treated cells. Histamine release induced by both HRA+ sera and anti-IgE were inhibited by genistein, and Ca2+/Mg2+ depletion but not by bisindoylmaleimide. HRA+ sera induced prominent HR from normal basophils with little surface IgE, but induced no increased HR from basophils unresponsive to anti-IgE. CONCLUSIONS Up to 61% of CIU sera will induce increased HR from normal basophils in a sufficiently sensitive assay system. HR induced by most HRA+ sera is more prominent in basophils with very little surface IgE. However, there may be similar post-binding intracellular activation pathways following stimulation by HRA+ sera and anti-IgE.