With a model in which CBA T cells cause lethal graft-versus-host disease (GVHD) in irradiated B10.BR mice (H-2-compatible mice that express multiple minor histocompatibility antigen [HA] differences), information was sought on whether the induction phase of GVHD to minor HA is H-2 restricted. When unprimed CBA (H-2k) T cells were recirculated from blood to lymph for 1 d through irradiated H-2-compatible B10.BR or B10.K mice, the T cells underwent specific negative selection to the minor HA of the host, i.e, the filtered T cells failed to cause GVHD after transfer to B10.BR mice. With filtration through totally H-2-different B10 (H-2b), B10.D2 (H-2d), or B10.S (H-2s) mice, by contrast, no selection occurred, i.e., the filtered cells were unimpaired in their capacity to kill B10.BR mice. Selection was marked after filtration through H-2-semiallogeneic (B10 X CBA)F1 mice. These data, together with the results of filtering T cells through various H-2 recombinant strains, indicated that selection depended upon the donor and filtration host sharing determinants encoded by both the K- and D-ends of the H-2 complex. Compatibility only in the I region failed to cause demonstrable selection.