Mice made unresponsive to human γ-globulin demonstrate a marked cross-tolerance to porcine γ-globulin and equine γ-globulin but react normally to the more phylogenetically distinct chicken γ-globulin. This cross-tolerance exists in spite of an antigenic cross-reactivity at the indirect plaque-forming cell level of only 1 to 3%. This cross-tolerance status can be transferred to thymectomized, irradiated, bone marrow-reconstituted recipients by tolerogen-treated thymus cells. It is suggested that antigen recognition by the thymus-derived cell manifests a wider range of cross-reactivity than that evidenced by the bone marrow-derived cell.