We report the case of a vesiculopustular eruption associated with a transient myeloproliferative disorder (TMD) in a neonate with trisomy 21 syndrome. Examination of a skin biopsy showed a dermal mixed inflammatory infiltrate including atypical megakaryoblasts. As the white blood cell count spontaneously normalized, the eruption disappeared. This case report and review of the literature demonstrates that a vesiculopustular eruption could be an important clue to identify TMD in a neonate.