DA rats grafted with major histocompatibility complex-incompatible PVG heart grafts and treated with cyclosporine (CY) for 10 d do not reject their grafts, and develop a state of specific unresponsiveness toward PVG allografts. Cells from these animals tested in an adoptive transfer assay were incapable of restoring PVG graft rejection, and capable of specifically inhibiting the capacity of adoptively transferred normal lymph node cells (LNC) to do so. They effected third party Wistar/Furth (W/F) graft rejection, however. Adoptive transfer assays with purified subpopulations of the lymphocytes that mediated this effect showed that W3/25+ T cells of the helper/inducer subclass, when injected alone, failed to restore rejection, and were also able, when injected with normal LNC or the W/25+ cells separated from them, to prevent these cells from effecting rejection. MRC OX8+ T cells of the cytotoxic/suppressor subclass, B cells, and serum from rats with long-surviving grafts all failed to inhibit the allograft responsiveness of normal LNC, and thus were not identified as mediators of the state of specific unresponsiveness. These results show that the specific unresponsiveness that develops in rats with long-surviving grafts, and which, in part at least, is responsible for prolonged graft survival, is due to an alteration in the alloreactivity of the helper/inducer subclass of T cells. These cells not only lack the capacity to initiate a rejection response against the alloantigens of the graft, but also have the ability to inhibit the capacity of normal W3/25+ cells to do so.