A transient leukemoid reaction in a neonate with Down syndrome is reported. The blastic proliferation was identified as T lymphoblastic in an early stage of maturation (prethymocytes) using morphological, cytochemical, and immunological methods. A spontaneous complete remission occurred in 8 weeks. No additional cytogenetic alterations were found, except for those concerning chromosome 21. Other cases reported in the literature reveal that cytogenetic studies may be useful to distinguish these transient leukemic reactions from true leukemias in newborns with Down syndrome. The in vitro growth pattern of peripheral blood and bone marrow may also be useful for this purpose.