To determine the mechanism of the aplastic crisis in a patient with autoimmune hemolytic anemia (AIHA) and reticulocytopenia who developed red cell aplasia simultaneously, serum- and IgG-separated fractions were examined for the presence of erythroid progenitor cell inhibitors. The patient's red cell autoantibody was a complement-independent IgG that reacted with the little-e antigen of the Rh complex. A complement-dependent serum IgG inhibitor directed against erythroid colony- and burst-forming units but not granulocyte-macrophage units was detected in samples before treatment with extracorporeal staphylococcal protein-A immunoadsorption and corticosteroids. The erythroid progenitor cell inhibitor persisted in samples multiply adsorbed against type-ee red cells and was not detected in heat eluates prepared from these red cells. A reticulocytosis occurred when serum IgG levels were reduced to 27% of pretreatment values. At this point, the erythroid progenitor cell inhibitor was not detectable in vitro. These findings suggest that the development of the aplastic crisis in some patients with AIHA may be associated with the presence of two distinct IgG antibodies, one directed at the mature red cell and the other at the erythroid progenitor cells.