Third-party skin allografts were employed to test the specificity of transplantation tolerance achieved by neonatal inoculation of cells bearing H-2 alloantigens. Tolerant animals rejected with normal vigour third-party grafts expressing strong Class I alloantigens foreign to the host and to the donor of the tolerance-conferring inoculum. However, these animals rejected with exceptional vigour third-party grafts expressing weak Class II alloantigens plus the tolerated Class I alloantigen; even third-party grafts comprised of the host's own Class II antigens in conjunction with the tolerated Class I alloantigen were acutely rejected. It is proposed, but there is no direct evidence to prove, that rejection of these third-party grafts is mediated by killer T cells directed at the tolerated Class I alloantigens and that these cells are activated by the presentation of the putative tolerogen in an inappropriate I region context. Inconsistency of these data with a clonal deletion mechanism is discussed.