This is the report of a newborn with Down syndrome diagnosed with transient myeloproliferative disorder (TMD) that required chemotherapy on the first day of life. Children with Down syndrome have a 10- to 20-fold increased risk of developing TMD. TMD is characterized by an uncontrolled proliferation of myeloblasts in the infant's peripheral blood and bone marrow. In most instances, this unique disorder has the ability to spontaneously “turn off” the overproliferation and enter a state of remission. Only supportive care is recommended for TMD during the first months of life unless the clinical condition requires intervention. As more cases of this baffling disorder are presented, it is important to share our experience to aid in management and diagnosis.