To study the role of trisomy 21 in hematologic malignancies, we investigated the hematologic disorders of 13 patients with acquired trisomy 21 and 13 individuals with Down syndrome (DS). The most common hematologic malignancy among the patients with acquired trisomy 21 involved both granulocytic and monocytic lineages. By comparison, the hematologic disorders among the DS patients were predominantly acute lymphocytic leukemia and acute megakaryocytic leukemia. Although our sample was small, our results suggest that most patients with acquired trisomy 21 have different hematologic disorders than individuals with DS. Perhaps the role of trisomy 21 in the development of hematologic malignancy is different in constitutional trisomy 21 than it is in acquired trisomy 21.