Human monocytic ehrlichiosis (HME) is a tick-borne disease caused by Ehrlichia chaffeensis. Patients exhibit diagnostically important hematological changes, including anemia and thrombocytopenia, although the basis of the abnormalities is unknown. To begin to understand these changes, we used a mouse model of ehrlichiosis to determine whether the observed hematological changes induced by infection are associated with altered hematopoietic activity. Infection with Ehrlichia muris, a pathogen closely related to E. chaffeensis, resulted in anemia, thrombocytopenia, and a marked reduction in bone marrow cellularity. CFU assays, conducted on days 10 and 15 postinfection, revealed a striking decrease in multipotential myeloid and erythroid progenitors. These changes were accompanied by an increase in the frequency of immature granulocytes in the bone marrow and a decrease in the frequency of B lymphocytes. Equally striking changes were observed in spleen cellularity and architecture, and infected mice exhibited extensive extramedullary hematopoiesis. Splenomegaly, a characteristic feature of E. muris infection, was associated with an expanded and disorganized marginal zone and a nearly 66-fold increase in the level of Ter119(+) erythroid cells, indicative of splenic erythropoiesis. We hypothesize that inflammation associated with ehrlichia infection suppresses bone marrow function, induces the emigration of B cells, and establishes hematopoietic activity in the spleen. We propose that these changes, which may be essential for providing the innate and acquired immune cells to fight infection, are also responsible in part for blood cytopenias and other clinical features of HME.