Objective - mpl-/- mice have a profound defect in platelets and megakaryocytes and a defect in hematopoietic progenitor cells and stem cells. However, no specific subset of the progenitor/stem cell compartment has been shown to be particularly affected by this deficiency in mpl-/- mice. In this article, we identified a specific subset of bone marrow progenitor/stem cells that was altered in mpl-/- mice. Materials and Methods - In vitro and in vivo hematopoietic assays were utilized to examine the response to interleukin-11 in mice lacking the receptor for thrombopoietin (TPO) (mpl-/- mice). Results - The interleukin (IL)-11-responsive subset of progenitor cells was not detected in clonal cultures of bone marrow cells from mpl-/- mice. However, mpl-/- mice responded to IL-11 in vivo as evidenced by a rise in platelet count and an increase in spleen weight. Experiments were performed to address this paradox: administration of 5-fluorouracil with consequent expansion of early hematopoietic cells resulted in the appearance of IL-11-responsive cells in mpl-/- mice when assayed in in vitro cultures. Conclusion - Thus, although mpl-/- mice have the capacity to produce IL-11-responsive progenitor cells, under steady state conditions their expansion is dependent on TPO. This is the first evidence that a specific subset of bone marrow progenitor/stem cells is altered in mpl-/- mice.