AMKL is a rare subtype of acute myelogenous leukemia. In children, AMKL frequently develops in patients with Down syndrome (DS-AMKL). Until now, few large series of childhood AMKL have been reported. We reviewed 43 children with AMKL diganosed between 1987 and 2005 at Nagoya University Hospital and Japanese Red Cross Nagoya First Hospital. The diagnosis of AMKL was established on the basis of cell morphology and was confirmed by the positivity of immunophenotyping against CD41 and CD36. The diagnosis for several patients was also confirmed by platelet peroxidase staining using an electron microscope. The morphology of blast cells was categorized into three groups according to the stage of cell maturation: type 1 = completely undifferentiated blasts; type 2 = intermediately differentiated blasts with characteristic blebs; and type 3 = blasts with dysmegakaryocytopoiesis, including the presence of micromegakaryocytes. Twenty-five patients (58%) had DS-AMKL and 18 (42%) had de novo AMKL. The median age was 20 months (range, 8–38 months) for DS-AMKL and 12 months (range, 2–185 months) for de novo AMKL. The ratio of boys to girls was 1: 0.8 for DS-AMKL and 0.5:1 for de novo AMKL. The initial white blood cell count and lactic dehydrogenase levels were much higher in patients with de novo AMKL than in those with DS-AMKL. The morphology of blast cells in DS-AMKL and de novo AMKL were distributed as follows: type 1 (67%, 57%), type 2 (24%, 43%), and type 3 (9%, 0%), respectively. The results of immunophenotyping in the DS-AMKL and de novo AMKL group, respectively, were as follows: CD41 (88%, 87%), CD7 (96%, 70%), CD33 (84%, 90%), Gly (67%, 0%), and CD34 (70%, 20%). Cytogenetic studies were performed for 23 patients with DS-AMKL and 18 patients with de novo AMKL. Normal karyotype including +21 in DS-AMKL was noted in 5 patients with DS-AMKL and in 1 patient with de novo AMKL. Numerical chromosomal anomalies were common in both groups. Patients with DS-AMKL had +8 (4 patients), additional +21 (1 patient), and −7/del(7q) (6 patients). Patients with de novo AMKL had +8 (5 patients), +21 (7 patients), and −7/del(7q) (2 patients). The specific AMKL-associated translocation such as t (1:22) was noted in 2 patients with de novo AMKL and 3q21q26 was noted in 1 patient with de novo AMKL. In patients with DS-AMKL, 24 of 25 (96%) achieved complete remission. Relapse occurred in 2 patients, and 2 different patients died of cardiac problems. Of the 25 patients with DS-AMKL, 21 (84%) are currently surviving. Of the 18 patients with de novo AMKL, 12 of 17 (71%) patients achieved complete remission. One patient did not receive induction therapy. Thirteen patients received stem cell transplantation (allogeneic, 6; autologous, 7), and 13 of 18 patients (72%) are currently surviving. The estimate of 5-year survival was 83.3% for patients with DS-AMKL and 71.8% for patients with de novo AMKL (p=0.38). Our study shows the diverse heterogeneity of childhood AMKL and the need for subclassification according to megakaryocytic maturation. The blast cells seem more immature in DS-AMKL than in de novo AMKL in terms of morphology and immunophenotyping. The prognosis of DS-AMKL is excellent. Although prognosis of de novo AMKL was very poor in previous studies, our results using stem cell transplantation are promising.