In this study we established that the conjugate of ovalbumin (OVA), which was used as a model allergen, with monomethoxypolyethylene glycol (mPEG), i.e., OVA(mPEG)11, was not only tolerogenic and essentially non-allergenic, but also capable of inactivating mast cells sensitized with anti-OVA IgE antibodies (Abs). Moreover, mast cells sensitized with a mixture of anti-OVA and anti-DNP IgE Abs were also desensitized by OVA(mPEG)11 with respect to both sensitivities. Most importantly, treatment of OVA-sensitive mice by OVA(mPEG)11 protected them from systemic anaphylaxis on challenge with OVA. The possibility of inactivating IgE-sensitized mast cells with mPEG conjugates of single epitopes of a given allergen is being investigated.