We have constructed bone marrow irradiation chimeras to investigate the influence of self antigens on the specificity of the T lymphocyte receptor repertoire. Bone marrow cells from (A × B)F1mice heterozygous for the major histocompatibility genes were allowed to mature into T cells in irradiated parent A or parent B strains. More than 8 weeks after irradiation, when the lymphoid system had regenerated from the F1stem cells, the degree of T cell reactivity to mutant major histocompatibility antigens, A′, was assessed. It was found that T cells that had matured in the irradiated A mice, F1→ A chimeras, responded better to A′antigen than did T cells from the F1→ B chimeras. Because the mutant histocompatibility antigen A′is very similar in structure to A, differing only by one or a few residues, this suggests that the T cell repertoire in F1→ parent chimeras reacts preferentially with foreign antigens that are slight variants of the self antigens expressed on radiation-resistant cells--probably cells in the thymus.