Graft-vs.-host (GVH)-related immunosuppression has previously been demonstrated in F1 rodent recipients of parental lymphoid cells, and has been thought to result from an immunologic attack of the donor against the host. Since all cells of such F1 recipients could potentially bear target class I MHC alloantigens, it has not previously been possible to determine precisely the target tissues responsible for development of GVH-related effects. In the present studies we have used mixed allogeneic chimeras as recipients of host or donor-strain lymphocyte inocula, and have made the surprising observation that "GVH-induced" immune unresponsiveness does not require GVH reactivity, per se, but develops in the presence of a one-way alloresponse against lymphohematopoietic cells in either the GVH or the host-versus-graft direction.