The direct effect of cyclophosphamide (CY) on bone marrow and liver stromal cells of DBA/2 and C57BL/6 mice after a single intraperitoneal dose of 300 mg/kg, was assessed. Ultrastructural observations were carried out 2,4,6,12,18, and 24 h and 2,3,5,7,10,15,22 and 30 days after CY in femoral bone marrow and liver fixed by immersion or vascular perfusion. A massive depletion of hemopoietic cells was observed in bone marrow as early as 12 h after CY treatment, and normality was recovered only after 10 days. Among stromal cells, sinus endothelial cells, reticular cells, and macrophages were particularly sensitive to CY and showed severe damage as soon as 2 h after treatment. There was also an important dilatation of sinusoids, and the presence of mature red cells in the hemopoietic parenchyma, and macrophages and immature cells in the lumen and in circulating blood demonstrated the loss of integrity of the endothelium. In the liver, injured cells showing vesiculation and disruption of endothelial and Kupffer cells of sinusoids were evident 6 h after CY. The alterations caused by CY were transient. Although recovery of the hemopoietic cells in bone marrow and liver was achieved by day 10, the stromal cells showed damage even 15 days after CY, and a return to normality was only reached on day 30. Thus, the effect of CY on stromal cells, that was longer lasting than the effect on the hemopoietic compartment, demonstrated a higher recovery capacity of hemopoiesis with respect to stromal cells. These results demonstrate that recovery of hemopoiesis occurred even while the severe damage inflicted by CY to the stromal cells remained unrepaired.