We report two neonates with Down syndrome and postnatal leukemoid reactions who developed acute widespread pustular eruptions. The white blood cell (WBC) counts on the first day of life were markedly elevated, with blasts seen on examination of the peripheral blood smear. The skin eruptions progressed and became pustular. Viral and bacterial cultures were negative. Skin examination revealed pustules on an erythematous base on the cheeks, shoulders, trunk, and proximal extremities. Skin biopsy specimens showed an intraepidermal pustule with an inflammatory infiltrate including neutrophils, eosinophils, and mononuclear cells. The mononuclear cells had atypical, immature-appearing nuclei. In patient 1, these cells were strongly myeloperoxidase positive on immunohistochemistry, indicating myeloid lineage. In patient 2, these cells were CD3-positive T cells. Patient 1 received a 5-day infusion of continuous cytarabine (ara-C) secondary to high WBC counts and symptomatic hyperviscosity. During therapy, the high WBC count and the pustules resolved. The lesions of patient 2 improved with topical mometasone furoate and resolved as her WBC count decreased. Recently, similar cases have been reported. Transient myeloproliferative disorders, or leukemoid reactions, should always be considered when newborns with Down syndrome or trisomy 21 mosaicism develop a pustular eruption.