The mechanism of anemia in four patients with transient red cell aplasia of childhood ("erythroblastopenia") was studied at the time of diagnosis by assessing the colony growth of marrow erythroid progenitors in methylcellulose tissue cultures. Marrow from Patient 1 yielded high normal numbers of BFU-E colonies that were completely abolished on addition of autologous serum or IgG. Patient 2 had normal BFU-E growth that markedly declined when autologous serum or IgM was added to the cultures, but growth remained unchanged with added autologous IgG or peripheral blood mononuclear cells (PBMC). Marrow from Patient 3 yielded low CFU-E and BFU-E numbers with standard plating techniques, but colonies strikingly increased when marrow fractions from an albumin density gradient were cultured. PBMC from Patient 3 suppressed control marrow CFU-E and BFU-E, but serum had no effect. Patient 4 had normal CFU-E and BFU-E that increased with autologous serum and remained unchanged with autologous PBMC. We conclude that the red cell aplasia in Patients 1, 2, and 3 was due to suppressed erythropoiesis via IgG, IgM, and cellmediated inhibition, respectively. In contrast, in Patient 4 no immune mechanism was demonstrated. Whereas transient red cell aplasia has a uniform clinical presentation, there are at least four pathogenetic mechanisms that can be detected in vitro.