Subsequent to systemic administration of doxorubicin or whole-body X-irradiation, C57BL/6 mice exhibit a depletion in lymphoid cells (macrophages) lasting 2-3 weeks and returning to normal by 4 weeks after either treatment. We evaluated the ability of repeated oral administration of the synthetic macrophage activator muramyl tripeptide phosphatidylethanolamine (MTP-PE), either in free form or encapsulated into multilamellar liposomes, to reverse or prevent the decline in macrophages after cytoreductive therapies. The number of both resident peritoneal macrophages and peritoneal exudate cells elicited by thioglycollate-induced inflammation increased after the oral administration of MTP-PE (three times a week) for at least 3 weeks. The depletion of macrophage number from the peritoneal cavity that occurred after two IV injections of doxorubicin or X-irradiation with 1.5 or 3.0 Gy was prevented by repeated oral feedings of MTP-PE. Moreover pretreatment of mice with oral MTP-PE prevented depletion of macrophages resulting from IV injections of doxorubicin. Modest protection was also noted for blood leukocytes in mice receiving oral MTP-PE following systemic DXR. Similar effects were achieved when MTP-PE was encapsulated into phospholipid liposomes: this formulation also allowed macrophages to be readily activated to the tumoricidal state. The oral administration of MTP-PE offers an additional strategy for protection of host defense cells during cytoablative therapies.