MicroRNAs (miRNAs) control basic biological functions and are emerging as key regulators of haematopoiesis. This study focused on the functional role of MIRN155 on megakaryocytic (MK) differentiation of human cord blood CD34+ haematopoietic progenitor cells (HPCs). MIRN155, abundantly expressed in early HPCs, decreases sharply during MK differentiation. Functional studies showed that enforced expression of MIRN155 impairs proliferation and differentiation of MK cells. Furthermore, HPCs transfected with MIRN155 showed a significant reduction of their MK clonogenic capacity, suggesting that down-modulation of this miRNA favours MK progenitor differentiation. Consistent with this observation, MIRN155 downregulates, by directly binding to their 3'-UTR, the expression of Ets-1 and Meis1, two transcription factors with well-known functions in MK cells. These results show that the decline of MIRN155 is required for MK proliferation and differentiation at progenitors and precursors level and indicate that sustained expression of MIRN155 inhibits megakaryopoiesis.