Infants with Down's syndrome have an increased incidence of acute nonlymphocytic leukemia (ANLL). They are also at risk of developing a transient myeloproliferative syndrome indistinguishable from ANLL except by its eventual clinical recovery. The authors studied five infants with Down's syndrome and leukocytosis with circulating blast forms in their peripheral blood with in vitro cultures of bone marrow colony forming units-granulocyte macrophage (CFU-GM), cytogenetics and peripheral blood neutrophil alkaline phosphatase (NAP) score. Three children developed ANLL, the other two had a transient myeloproliferative syndrome. The in vitro assay for CFU-GM showed abnormal results consistent with ANLL in the children who develop this disorder. Serial cytogenetic studies disclosed the appearance of an abnormal clone in one patient. A combination of clinical parameter in vitro colony studies and cytogenetic studies in these children was helpful in distinguishing ANLL from a myeloproliferative disorder. The NAP scores were not helpful.