The congenitally athymic nude (nu/nu) mouse was studied as a model for amebic liver disease, using Entamoeba histolytica. Despite intrahepatic inoculation of massive numbers of amebae, we could not produce sustained infections in nu/nu mice. We also failed to induce hepatic amebiasis in thymus-intact nu/+ and +/+ littermates, or in nu/+ mice pretreated with rabbit antimouse thymocyte globulin. Humoral response was measured in both the nu/nu and nu/+ mice. Nu/+ but not nu/nu animals developed a specific IgG response after challenge with E. histolytica. There were no significant IgM responses. Pretreatment with silica increased susceptibility of both nu/nu and nu/+ mice to development of liver abscesses. These studies suggest that host resistance in murine amebiasis is critically dependent upon the macrophage, but not upon T cell-mediated defenses.