Neonates with Down Syndrome (DS) have a greater predisposition to Transient Myeloproliferative Disorder (TMD), a hematologic disorder with transient proliferation of immature cells in peripheral blood and bone marrow. Some neonates with TMD present with skin manifestations characterized by diffuse erythematous papules, with crusts, vesicles and pustules, usually with early and prominent facial involvement. Despite the spontaneous remission of TMD over several months, some cases may need support care and, occasionally, chemotherapy. It is described the case of a newborn with Down Syndrome phenotype, male, that manifested such characteristics in the fifth day of life, and the instituted propaedeutics in a Neonatal Intensive Care Unit. The diagnosis is both clinical and laboratorial, and therefore was based in typical features. The used treatment involved conservatory measures of skin and mucosal care, avoiding trauma. It was observed an improvement of all lesions within one month of life. As a result, it is demonstrated the importance of differential diagnosis given the need for regular clinical follow up and eventually chemotherapy.