Transient abnormal myelopoiesis (TAM) is a pre-leukaemic syndrome associated with Trisomy 21 (Down syndrome). TAM typically regresses without treatment, but if needed TAM cells are exquisitely sensitive to a short course of low-dose cytarabine (LDAC). A significant minority of TAM patients progress to myeloid leukaemia of Down Syndrome (MLDS) requiring intensive chemotherapy. We describe a neonate with unusually recalcitrant TAM who required four 7-day courses of LDAC. Neonates with Down syndrome are at significant risk of severe toxicity from chemotherapy but this was mitigated by the use of repeated courses of LDAC, without the need for more intensive MLDS treatment.