A goal of transplantation immunology is to be able to induce antigen-specific tolerance in transplant recipients. In the present study we describe an in vivo model of antigen-specific transplantation tolerance to skin allografts using mice congenic at Qa1, a ubiquitously expressed class I-like molecule encoded to the right of H-2D. B6 mice are deficient in Qa1a-specific T-helper cells and only reject Qa1a disparate tail skin grafts when a second graft expressing additional helper determinants is also present. We report that animals initially engrafted with Qa1a disparate skin, in the absence of any source of additional help, are rendered tolerant to Qa1a disparate skin allografts despite the subsequent presence of inducer skin grafts expressing additional helper allodeterminants. The nonresponsive state is Qa1a-specific, because HY-bearing inducer grafts are rejected normally. In vitro, Qa1a-tolerant animals are specifically unable to generate anti-Qa1a T-killer cells, which provides the cellular basis for their failure in vivo to reject Qa1a skin allografts. Thus, initial exposure to Qa1a allodeterminants, in the absence of T-cell help, leads to a state of Qa1a-specific transplantation tolerance. This study suggests that antigen-specific transplantation tolerance may be induced by exposing naive T-killer cells to tissue alloantigens under conditions in which T-cell help is not generated.