Mice lacking thrombopoietin (TPO) or its receptor c-Mpl are severely thrombocytopenic, consistent with a dominant physiological role for this cytokine in megakaryocytopoiesis. However, these mice remain healthy and show no signs of spontaneous hemorrhage, implying that TPO-independent mechanisms for platelet production exist and are sufficient for hemostasis. To investigate the roles of cytokines that act through the gp130 signaling chain in the residual platelet production of mpl^-/- mice, mpl^-/-IL-6^-/-, mpl^-/-LIF^-/-, andmpl^-/-IL-11R^-/-double-mutant mice were generated. In each of these compound mutants, the number of circulating platelets was no lower than that observed in mice lacking only the c-mpl gene. Moreover, the deficits in the numbers of megakaryocytes and megakaryocyte progenitor cells in the bone marrow and spleen were no further exacerbated inmpl^-/-IL-6^-/-,mpl^-/-LIF^-/-, ormpl^-/-IL-11R^-/-double-mutant mice compared with those in Mpl-deficient animals. In single IL-6^-/-, LIF^-/-, andIL-11R^-/- mutant mice, platelet production was normal. These data establish that, as single regulators, IL-6, IL-11, and LIF have no essential role in normal steady-state megakaryocytopoiesis, and are not required for the residual megakaryocyte and platelet production seen in thec-mpl^-/- mouse.