Normal and immune mice were evaluated for their ability to resist infection to the rodent malaria parasite, Plasmodium yoelii, during pregnancy. Parasitemia levels were slightly higher and time-to-death shorter in the nonimmunized pregnant group infected with virulent parasites relative to virgin controls. Subinoculation experiments revealed that numerous virulent organisms were present in the placentas of unprotected gravida but were absent from the fetal livers of their conceptuses. It was also found that mice preimmunized with irradiated P. yoelii survived a usually lethal challenge infection during midgestation and delivered healthy newborns. Associated with this protection against transplacental spread of parasites was the additional key finding that placental macrophages were as effective as peritoneal exudate cells in phagocytosing parasite derived material in vitro. This murine malaria-pregnancy model should provide new insights on the various factors (virulence, immunogenicity) of microbial infections affecting the fetal-maternal relationship, as well as on the expression of immune effector mechanisms and immunoregulation, during the reproductive process.