An experimental murine model of bone marrow transplantation (BMT) has been used to study the mechanisms of platelet production following transplantation. A defined primitive population of hematopoietic bone marrow cells (1000 Lin-Sca-1+) was isolated and transplanted into lethally irradiated (13 Gy) syngeneic recipient mice. Platelet counts, but neither red nor white blood cell (WBC) counts, were low 30 days after transplantation. By 90 days, platelet levels had normalized in transplanted mice, but this occurred from a reduced megakaryocyte progenitor (CFU-Mk) pool, implying that altered bone marrow control was involved in platelet production. To assess the capacity of the bone marrow of these compensated mice to sustain platelet production, the rate and degree of recovery were examined following administration of 150 mg/kg of 5-fluorouracil (5-FU) 90 days after transplantation. Transplanted mice showed a delay, both in platelet recovery and rebound thrombocytosis, after 5-FU administration when compared to normal littermates treated with 5-FU. The regeneration and expansion of bone marrow CFU-Mk and mature megakaryocytes was retarded in the transplanted mice and explained the altered platelet kinetics. The onset of increased platelet and mature megakaryocyte size, however, was not different between the two groups, indicating that the transplanted mice responded normally to the mechanisms controlling megakaryocyte development and platelet formation. The data suggest that following BMT a limitation in the proliferative capacity of primitive hematopoietic cells results in a smaller pool of megakaryocyte precursors. Compensatory adjustment within the megakaryocyte lineage, nevertheless, results in normalization of megakaryocyte and platelet number. The ability of transplanted mice to sustain platelet production when challenged with increased platelet demand is not limited by megakaryocytic maturation but by a restriction in proliferation or differentiation from the stem cell pool.