Several reports indicated that a circulating serum inhibitor (antibody) is involved in the pathogenesis of acquired pure red cell aplasia (PRCA). The pathophysiologic significance of this inhibitor was assessed according to the status of erythroid progenitor cells in the bone marrow. Direct proof for the antibody acting against erythroid stemcells was lacking. Employing an in vitro assay, erythroid colony forming cell (CFU-e) numbers in PRCA marrow were quantified and the cytotoxic effect of PRCA serum on CFU-e was investigated. The CFU-e population size in the marrow of PRCA patients was severely reduced; the relative number of myeloid colony forming cells was normal. The serum was demonstrated to contain a factor which was cytotoxic to CFU-e, in the presence of complement [C]. Inhibition of erythropoiesis in PRCA is achieved by a C dependent plasma factor which eliminates or inactivates CFU-e and which constitutes an effective block at the precursor cell level in the differentiation pathway of the erythroid line.