Hrs binding protein (Hbp) tightly associated with Hrs is thought to play a regulatory role in vesicular trafficking during endocytosis and exocytosis. In this study, we have expressed dominant-negative mutants of Hbp to evaluate their effects on the degranulation of secretory granules in RBL-2H3 mast cells. The dominant-negative mutants of Hbp significantly inhibited IgE receptor (Fc epsilon RI)-triggered secretory response as tested by beta -hexosaminidase release. These results suggest that Hbp functions as a regulator in the Fc epsilon RI-triggered degranulation of secretory granules in mast cells.