In this electron microscopic study, erythropoiesis in mice was completely suppressed by repeated hypertransfusion for up to 6 wk. We describe a sequence of ultrastructural changes in the marrow's stromal cells that accompany the resulting shift from erythropoietic to granulopoietic tissue. These include the destruction of medullary macrophages, the accelerated development of marrow adipocytes and reticular cells, and a reduction in the amount of vascular space in the marrow. The absence of macrophages was highlighted by the complete lack of erythrophagocytosis in the marrows of hypertransfused mice that were injected with the hemolysing agent, phenylhydrazine. The changes in the marrow stroma probably underlie the shift in the marrow's hematopoietic microenvironment. Repeated phlebotomy of mice that had been hypertransfused for 2 wk evoked the appearance of unique stromal cells in the marrow, similar to cells that have been associated with accelerated erythropoiesis. The newly anemic mice were otherwise unable to mount an erythropoietic response to repeated bleeding, showing that the decline in the erythropoietic microenvironment brought on by sustained hypertransfusion was a lasting one.