Our previous findings that antigens, such as ovalbumin (OA) and the extract of ragweed pollen (RAG), could be rendered nonantigenic, nonallergenic and tolerogenic by conjugation with polyethylene glycol (PEG) have been extended in the present study to the synthesis of conjugates of a variety of antigens with monofunctional monomethoxy-PEGs (mPEGS) of different molecular weights by the use of the mixed anhydride method. Thus, mPEGs with molecular weights of 2,000, 5,000, 10,000 and 20,000 were coupled to proteins such as dog serum albumin (DA), bovine pancreatic ribonuclease, OA and the constituents of pollen, helminth and bacterial allergens (RAG, Timothy grass pollen, Ascaris suum and Micropolyspora faeni). All these mPEG conjugates depressed markedly the ongoing IgE antibody formation in sensitized animals, in spite of additional injections of the sensitizing dose of the appropriate antigen. Moreover, the allergenicity of the proteins was either totally abolished or markedly reduced after coupling to mPEGs. Conjugates of DA and OA of varying degree of substitution (i.e. number of mPEG molecules attached per protein molecule) were prepared with mPEGs of different molecular weights and their immunological properties were assessed. It appears that, for a series of tolerogenic conjugates of the same antigen, there exists some inverse relationship between the degree of substitution and the molecular weight of mPEG, i.e. a high level of tolerogenicity with a concomitant reduction or total loss of allergenicity was achieved with a lower degree of substitution utilizing mPEGs of increasing molecular weights. On the basis of these results, it is concluded that a variety of allergens may be converted by conjugation with mPEGs to tolerogenic products with a potential for use in the therapy of patients allergic to a wide spectrum of common allergens.