A 3-year-old patient presented with anemia, thrombocytopenia, and blasts in the peripheral blood. A bone marrow aspirate revealed a myelodysplastic syndrome (MDS). A mosaic abnormal female karyotype 46,XX, t(1;19)(q42; p13.1)c[12]/ 47,idem,+21c[3]/ 47,idem,-7,+21c,+mar[7] was obtained on G-banded metaphases from unstimulated bone marrow aspirate cell culture. To rule out constitutional abnormalities, we performed a cytogenetic analysis on the patient's phytohemagglutinin-stimulated peripheral blood and cultured skin fibroblasts. A karyotype of 46,XX,t(1;19) (q42;p13.1)c was found in all 20 peripheral lymphocytes analyzed, confirming the constitutional origin of the translocation. In addition, 5 out of 50 cells from two separate cultures of the skin fibroblasts contained an extra chromosome 21. The presence of two cell lines in multiple cultures indicates that the patient is a true low-level mosaic for trisomy 21. Because of the finding of monosomy 7 and a marker chromosome only in the trisomy 21 clone, we conclude that the leukemic clone arose from a hematopoietic precursor with constitutional trisomy 21. It is also possible that the t(1;19) played some role in the development of the MDS. Because acute myelogenous leukemia (AML) and MDS with Down syndrome (DS) have distinct biologic and clinical features, the identification of DS patients with a mild or normal phenotype in the AML/MDS population is of fundamental importance for clinical diagnosis and management.