The transcription factor c-Myb and coregulator p300 have a key role in maintaining production of controlled numbers of megakaryocytes and platelets. In mice, mutations in c-Myb or p300 cause thrombocytosis in otherwise wild-type animals and can ameliorate the thrombocytopenia in mice lacking the thrombopoietin receptor, c-Mpl, a model for human congenital amegakaryocytic thrombocytopenia. To examine whether inhibition of c-Myb/p300 is effective in other models of thrombocytopenia, the effect of the c-Myb(Plt4) mutation on thrombocytopenia associated with reduced platelet life span in Bcl-X(Plt20/Plt20) mice was assessed, as were responses in c-Myb(Plt4) and/or p300(Plt6) mutant mice to thrombocytopenia associated with antiplatelet antibodies, chemotherapy, or bone marrow transplantation. Homozygosity of the c-Myb(Plt4) allele ameliorated thrombocytopenia associated with reduced platelet life span, and c-Myb(Plt4/+) mice exhibited more rapid than normal recovery from thrombocytopenia caused by antiplatelet serum or bone marrow transplantation. Recovery to pretreatment platelet levels was unaltered in 5-fluorouracil-treated c-Myb(Plt4/+) mice relative to wild-type controls, but enhanced platelet production during subsequent thrombocytosis was evident. More modest enhancement of platelet recovery after 5-fluorouracil or bone marrow transplantation was also evident in p300(Plt6/+) animals. The data suggest potential utility of c-Myb/p300 as a target for therapeutic intervention in thrombocytopenia of diverse origins.