Animal allergens are an important cause of asthma and allergic rhinitis. We designed and tested a chimeric human-cat fusion protein composed of a truncated human IgG Fcγ1 and the major cat allergen Fel d1, as a proof of concept for a new approach to allergy immunotherapy. This Fcγ-Fel d1 protein induced dose-dependent inhibition of Fel d1-driven IgE-mediated histamine release from cat-allergic donors' basophils and sensitized human cord blood-derived mast cells. Such inhibition was associated with altered Syk and ERK signaling. The Fcγ-Fel d1 protein also blocked in vivo reactivity in FcεRIα transgenic mice passively sensitized with human IgE antibody to cat and in Balb/c mice actively sensitized against Fel d1. The Fcγ-Fel d1 protein alone did not induce mediator release. Chimeric human Fcγ-allergen fusion proteins may provide a new therapeutic platform for the immune-based therapy of allergic disease.