A newborn with a karyotype of 47, XY, +21 presented at birth with a white blood cell count of 27 700/microL of which 61% were blast cells. The blast cell morphologic structure was initially not characteristic of any particular lineage, although the cytoplasm contained fine granules and occasional small vacuoles. Routine cytochemical stains were negative, except one for nonspecific esterase that was faintly positive in most of the blast cells. Flow cytometric analyses showed that the blast cells expressed glycophorin A with a subset dimly coexpressing CD45 and were negative for CD34, CD71, myeloid, lymphoid, and platelet-associated antigens. These immunophenotypic findings were consistent with an abnormal erythroid phenotype. A few days postpartum, markedly dysplastic erythroid precursor cells appeared in the peripheral blood and increased in number as the early blast cells decreased. After a period of subdued blast cell production, a second wave of increase in the number of blast cells and dysplastic erythroblasts followed and ended with the disappearance of circulating abnormal cells. The child is now 5 years old and no major illness has been reported since the remission of this disorder. This case most likely belongs to the category of transient myeloproliferative disorders, although the erythroid-like phenotype of blast cells and the evidence of single-lineage maturation to circulating dysplastic erythroid precursors allow the suggestion that this process could represent a special form of a self-limited hematologic disorder in Down syndrome.