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Two infants with Down syndrome had transient myeloproliferative disorder (TMD) during the neonatal period and subsequently acute nonlymphoblastic leukemia (ANLL). Histochemically, the blast cells in TMD were indistinguishable from those in ANLL. Only the constitutional chromosome (trisomy 21) was found in TMD, whereas new cytogenetic abnormalities emerged in ANLL. A mixed growth pattern in stem cell cultures during TMD suggested the existence of an abnormal clone that might be responsible for the evolution into ANLL at a later date. Serial cytogenetic studies and culture studies of peripheral blood cells may help to understand the pathophysiology and risk of ANLL in patients with TMD.