Transient leukemoid reactions that resemble acute leukemia have been well described for infants with trisomy 21 (Down syndrome). We report a phenotypically normal 3-day-old boy with hepatosplenomegaly, leukocytosis, and circulating myeloblasts. On chromosome analysis, trisomy 21 was found in all blood and bone marrow cells. However, only 4% of cultured skin fibroblasts were trisomic and the other 96% were normal, thus indicating mosaicism. Without treatment, the leukocyte count gradually returned to normal and the organomegaly diminished. Subsequently, chromosome analysis of blood and bone marrow disclosed a predominance of cells with a normal karyotype. These findings suggest that mosaicism could be responsible for the transient leukemoid reactions in some newborns--i.e., the trisomic cells may temporarily gain a proliferative advantage over the normal cells, perhaps by inhibiting their growth. Serial cytogenetic studies, as well as chromosome analysis of more than one tissue, may help to distinguish transient leukemoid reactions from acute leukemia in infants.