Recent concern has arisen about the development of neutralizing anti-erythropoietin (EPO) antibodies during the course of treatment with recombinant EPO. The underlying mechanisms are poorly understood. A patient was observed who developed wheals at the sites of subcutaneous injections of epoetin-alpha before the manifestation of pure red cell aplasia (PRCA). Intravenous application of different epoetins evoked skin reactions at the sites of former subcutaneous injections, indicating local persistence of sensitized cells, and eventually a systemic anaphylactoid response. Anti-EPO antibodies crossreactive with epoetin-beta and darbepoetin-alpha were demonstrated in patient serum. PRCA gradually improved after treatment with prednisolone.