Chimeric mice have been produced by various procedures such as neonatal injection of histoincompatible hemopoietic cells (1), fusion of eight-cell-stage embryos (2, 3), or X irradiation and reconstitution with allogeneic bone marrow cells (4, 5). Unresponsiveness to histocompatibility determinants has been assessed by measuring various parameters, among them skin allograft survival, graft-vs.-host (GVH)'reactivity, responsiveness in the mixed leukocyte reaction (MLR), and capacity to destroy appropriate target cells. The results obtained are not easy to interpret: some authors reported the specific absence of GVH-reactive cells in neonatally induced chimeras (6-8) and in contrast others demonstrated specific cytotoxic cells in neonatally induced chimeras (9, 10), bone marrow chimeras (11), and tetraparental or allophenic mice produced by fusion of embryos (12). On the basis of these findings some authors maintain that in chimeras tolerance is due to the absence or reactive cell clones whereas others postulate that tolerance is a manifestation of an active immune response leading to the production of blocking serum factors (9-11) or suppressor cells (13). It is difficult to reconcile the different results or interpretations, partly because of the different test systems used and also because the degree of lymphoid cell chimerism is missing in some reports (10, 12). In most studies on the induction of tolerance in lymphoid cell chimeras little attention has been given to the presence of immunocompetent T cells, either of host or donor origin. Thus, T cells of host origin would tend to reject the graft while donor T cells would induce a GVH reaction and thereby interfere nonspecifically with the immunocompetence of the host. To avoid this complication we have attempted to study tolerance in a situation where host and donor T cells are virtually absent, during the induction of chimerism. For this purpose lethally X-irradiated F, hybrid mice were repopulated with equal proportions of T-cell-depleted bone marrow cells from both parental strains. This procedure allows stem cell differentiation in the absence of mature functional T cells in a histoincompatible environment, a situation possibly resembling that of physiological stem cell differentiation where during the generation of immunocompetent cells self'-reactive cells arise and become tolerant. Lymphocyte reactivity in such mice for which we use the term" tetraparental bone marrow chimeras"(TBM) was studied in MLR as well as in T-cell-mediated lympholysis (CML).