The peak of erythropoietin-associated pure red cell aplasia (PRCA) incidents occurred over 4 years ago, but the debate on what triggered the autoimmune disorder continues today. The association with the recombinant human erythropoietin (epoetin, rhEPO) alpha-branded Eprex (Johnson and Johnson), makes PRCA of interest to medical and scientific communities, as well as the biotechnology industry, as it opens a broader question of the potential immunogenicity of biopharmaceuticals in general. An overview of the background and a perspective on current thought in erythropoietin-associated PRCA may assist in avoiding a repeat of similar immunogenic cases with other biopharmaceuticals and their emerging follow-on products. At the same time, it is also important to clarify what are the relevant questions to ask in order to ensure appropriate testing in the regulation of biopharmaceuticals. The upsurge of PRCA is associated with a formulation change introduced in 1998 when human serum albumin (HSA) as protein stabilizer was exchanged with polysorbate 80. Several explanations have been offered to explain how this change led to Eprex-associated PRCA. Leachates from uncoated rubber stoppers acting as adjuvant are blamed by the manufacturer of Eprex, but the experimental data substantiating this claim are poor and the leachates theory has no biological rationale and is also inconsistent with epidemiological and clinical data. A more likely explanation that is consistent with all data is a higher tendency for aggregate formation during handling and storage due to the exchange of HSA by polysorbate 80 as stabilizer.