In a previous study we showed that allografts of BN fetal bone, unlike allografts of adult bone, are not rejected by allogeneic recipients of the Lewis strain in spite of the existence of major histocompatibility complex (MHC) incompatibility between donors and hosts. In the present study, we analyzed the relationships existing between the host and fetal tissue that determine graft survival. We found that (1) the fetal BN graft, unlike adult grafts, induces in Lewis recipients a vigorous humoral response consisting mainly in the production of IgG antibody that seems to be directed against antigens of la-like specificities. (2) The BN rats are genetically defective in their capacity to respond to determinants and thus are not capable of producing anti-la antibodies; in accordance, Lewis fetal bone grafts are rejected by the BN recipients. (3) Chondrocytes isolated from fetal mouse bones do express la antigenic determinants. We suggest that the survival of an allogeneic fetal graft in an immunologically intact recipient depends on an active and selective immune response directed against the la components associated with the MHC on the embryonic and fetal cells. On the basis of these notions, we propose that the capacity of la determinants expressed on cells of the embryo, to elicit anti-la and IgG alloantibodies in the pregnant mother, determines the capacity of the embryo to escape rejection by the histoincompatible mother. In a previous study(1, 2)we demonstrated that one can successfully transplant orthotopically, in adult immunologically intact rats, allogeneic fetal bones derived from limbs of rat fetuses and thereby correct massive bone loss. Unlike adult-derived bone grafts, fetal bone grafts underwent processes of rapid ossification, bridging extensive bone defects and supporting the development of bone marrow. The striking conclusion from that work was that, unlike other adult allografts, the fetal bone escapes immune destruction in spite of the strong allogeneic barriers. This escape seemed puzzling in view of our observations that fetal bone grafts are not immunologically inert: we found that the tissue surrounding the allogeneic fetal bone graft became heavily infiltrated by lymphoid cells(1, 2). We had evidence that after transplantation the alloantigens of the fetal bone graft are recognized by T lymphocytes of the recipient, leading to the generation of alloantigen-specific helper T cells(1). In addition, we showed that the recipients of fetal bone grafts (unlike the recipients of adult bone) generate a high titer of specific alloantibodies. Thus, the striking resistance of fetal bone grafts to destruction and rejection by the host in spite of strong allogeneic differences contrasts with the generally accepted principles of transplantation genetics and allograft reactions. The phenomenon seemed puzzling in view of observations demonstrating that chondrocytes do express major histocompatibility antigens(3–6)in a manner similar to other cells of the body. Our aim, therefore, was to investigate the specific mechanisms involved in permitting the escape of a fetal bone allograft from rejection. This problem is of special interest because of its potential relevance to the escape of the allogeneic embryos and fetuses from destruction by the host immune system. It could then clarify aspects of fetomaternal relationships, as well as relations between an organism and its malignant tissues that carry fetal antigens.