In four patients with trisomy 21 (three constitutional, one acquired) with a morphological undifferentiated leukemia, diagnosis of erythroid leukemia was established by both immunophenotyping and ultrastructural studies. Indeed, a majority of blasts from three patients expressed several erythroid markers such as carbonic anhydrase 1, spectrin beta chain, and glycophorin A. In addition, band 3 and hemoglobin were immunologically detected in a fraction of the blast cells from two cases. At ultrastructural level, a majority or all blast cells exhibited erythroid differentiation features such as theta granules and ferritin molecules. However, platelet glycoproteins GP Ib, GP IIb, and GP IIIa were also immunologically detected in a fraction (from 14-82%) of the blasts. Since the ultrastructural study indicated that some promegakaryoblasts were also present in three patients, double labeling between erythroid markers (glycophorin A or carbonic anhydrase I) and platelet glycoprotein (Ib or IIIa) was performed and showed a clear overlap between the two kinds of markers. A similar approach was performed at ultrastructural level and indicated that blast cells with ultrastructural erythroid features of differentiation may have three distinct phenotypes, i.e., presence of glycophorin A without platelet glycoproteins or, conversely, the presence of platelet glycoproteins without glycophorin A and coexpression of glycophorin A and platelet glycoproteins. Expression of glycophorin A correlated directly with the differentiation level of the erythroid blasts, whereas platelet glycoproteins were essentially expressed in the more primitive leukemic erythroid cells. The GP Ib synthesized by these blasts was subsequently studied. The GP Ib alpha mRNA analyzed by Northern blot from these erythroid cells was identical in size with that from megakaryocytic cells as was the molecular weight of the GP Ib molecule from both after immunoprecipitation by a monoclonal antibody. Therefore, "in vivo" erythroid leukemic cells may express the main platelet glycoproteins including GP Ib.