Trisomy 21 is a common congenital disorder with well-documented clinical manifestations, including an increased risk for the transient myeloproliferative disorder as a neonate and leukemia in childhood and adolescence. Transient myeloproliferative disorder is only known to occur in hematopoietic cells with trisomy 21. Children with mosaic trisomy 21 also have a risk for hematological malignancies. We present a nondysmorphic neonate, with a negative noninvasive prenatal screening of maternal blood for trisomy 21, who came to medical attention because of ruddy skin. He was found to have mild polycythemia, thrombocytopenia, and developed peripheral blasts. His clinical presentation was consistent with transient myeloproliferative disorder, which is only seen with trisomy 21. Cytogenetic studies of peripheral blood are positive for mosaic trisomy 21.