IgE antibodies bind the high-affinity IgE Fc receptor (Fc epsilon RI), found primarily on mast cells and basophils, and trigger inflammatory cascades of the allergic response(1,2). Inhibitors of IgE-Fc epsilon RI binding have been identified and an anti-IgE therapeutic antibody (omalizumab) is used to treat severe allergic asthma(3,4). However, preformed IgE-Fc epsilon RI complexes that prime cells before allergen exposure dissociate extremely slowly(5) and cannot be disrupted by strictly competitive inhibitors. IgE-Fc conformational flexibility indicated that inhibition could be mediated by allosteric or other non-classical mechanisms(6-8). Here we demonstrate that an engineered protein inhibitor, DARPin E2_79 (refs 9-11), acts through a non-classical inhibition mechanism, not only blocking IgE-Fc epsilon RI interactions, but actively stimulating the dissociation of preformed ligand-receptor complexes. The structure of the E2_79-IgE-Fc(3-4) complex predicts the presence of two non-equivalent E2_79 sites in the asymmetric IgE-Fc epsilon RI complex, with site 1 distant from the receptor and site 2 exhibiting partial steric overlap. Although the structure is indicative of an allosteric inhibition mechanism, mutational studies and quantitative kinetic modelling indicate that E2_79 acts through a facilitated dissociation mechanism at site 2 alone. These results demonstrate that high-affinity IgE-Fc epsilon RI complexes can be actively dissociated to block the allergic response and suggest that protein-protein complexes may be more generally amenable to active disruption by macromolecular inhibitors.