Interaction of secretory IgE with Fc epsilon RI is the prerequisite for allergen-driven cellular responses, fundamental events in immediate and chronic allergic manifestations. Previous studies reported the binding of soluble Fc epsilon RI alpha to membrane IgE exposed on B cells. In this study, the functional interaction between human membrane IgE and human Fc epsilon RI is presented. Four different IgE versions were expressed in mouse B cell lines, namely: a truncation at the C epsilon 2-C epsilon 3 junction of membrane IgE isoform long, membrane IgE isoform long (without Ig alpha /Ig beta BCR accessory proteins), and both epsilon BCRs (containing membrane IgE isoforms short and long). All membrane IgE versions activated a rat basophilic leukemia cell line transfected with human Fc epsilon RI, as detected by measuring the release of both preformed and newly synthesized mediators. The interaction led also to Ca super(2+) responses in the basophil cell line, while membrane IgE-Fc epsilon RI complexes were detected by immunoprecipitation. Fc epsilon RI activation by membrane IgE occurs in an Ag-independent manner. Noteworthily, human peripheral blood basophils and monocytes also were activated upon contact with cells bearing membrane IgE. In humans, the presence of Fc epsilon RI in several cellular entities suggests a possible membrane IgE-Fc epsilon RI-driven cell-cell dialogue, with likely implications for IgE homeostasis in physiology and pathology