In the present work we show that acute infection of C3H mice with the CL strain of Trypanosoma cruzi is characterized by an exponential growth of parasites and high mortality accompanied by anemia, thrombocytopenia, leukopenia, and bone marrow hypoplasia. Administration of nifurtimox, a trypanocydal drug currently in clinical use at different days postinfection, modulates parasitemia and prevents mortality. More importantly, none of blood and bone marrow alterations were observed in nifurtimox-treated animals when treatment was initiated early in infection, one or seven days postinoculation. The bone marrow alterations were characterized by a decrease in the total number cells as well in the number of megakaryoblasts and erythroblasts. Transfer experiments of bone marrow cells from infected mice to noninfected lethally irradiated recipients revealed a poor marrow-repopulating activity. The colony forming units-spleen assay confirmed the depression of committed clonal progenitors cells and revealed a decreased number of granulocyte/macrophage, megacariocyte and erythrocyte colonies. In summary, this is the first report showing that acute T. cruzi infection results in profound alterations of the hematopoietic system and that these alterations can be prevented by nifurtimox treatment.