Intravenous injection of dichloromethylene diphosphonate (Cl2MDP) encapsulated in liposomes results in specific elimination of macrophages in the spleen and liver of normal mice. Severe combined immunodeficient (SCID) mice were treated with Cl2MDP-liposomes followed by injection of human peripheral blood leukocytes. Control SCID mice had no detectable human cells within 72 hours as determined by fluorescence-activated cell sorting (FACS) analysis. However, Cl2MDP-liposome-treated animals maintained a large proportion (%) of human cells in peripheral blood and spleen for at least 12 days. Cl2MDP-liposome-injected SCID mice that had previously been implanted with human fetal thymus and liver showed a transient increase in human cell content in peripheral blood, and an accumulation of human cells specific to the white pulp of the spleen. These results indicate that murine mononuclear phagocytic cells may play an important role in the clearance of human cells injected intravenously or generated endogenously in SCID mice and that Cl2MDP-liposome-mediated macrophage depletion allows human hematopoietic cells to circulate and survive in SCID mice, thereby expanding the potential for studying human cellular processes in vivo.