The role of donor and host H2D alleles in the graft-vs-host response was evaluated by measurement of DNA synthetic response of donor lymph node cells in lethally irradiated hosts and by a mortality assay in sublethally irradiated F1 hosts. Comparison of the potency of graded doses of B10.A, B10.A(2R), and (B10.A X B10.A(2R))F1 cells in (B10 vs B10.A)F1 and other hosts expressing foreign KbIb revealed a deficient response of 10(6) B10.A(2R) cells, but only when the host was heterozygous d/b at H2-D. Studies with TI congenic donors failed to implicate T region antigens in this effect. These results are interpreted to suggest that under the conditions of these experiments there is F1 hybrid resistance to alloaggressive T lymphocytes that are homozygous in the Db region.