Although the phenomenon of T cell-mediated suppression is well established, particularly in experimental models of transplantation, the mechanisms involved in this form of immunoregulation remain controversial. We have recently demonstrated, using an in vitro system, that anergic T cells can act as suppressor cells by competing for the membrane of the antigen-presenting cell (APC) and for locally produced interleukin-2. In the experiments described here we have explored the ability of anergic T cells to effect linked suppression in antigen-specific and allospecific responses. We observed that anergic antigen-specific CD4+ T cells can inhibit T cells restricted by a different major histocompatibility complex (MHC) class II molecule provided that both restriction elements are expressed by the same APC. In addition, anergic allospecific clones could also effect linked suppression since they could regulate not only T cells specific for the same alloantigen but also responder T cells with direct allospecificity for a second allogeneic MHC molecule or with indirect, self MHC-restricted allospecificity for a processed MHC class I alloantigen. Furthermore, the regulatory effect of the anergic T cells was dependent on cell contact, was not dependent upon irradiation, and was maintained during in vitro culture. These data demonstrate that linked suppression can be effected by anergic T cells in vitro. In the clinical context this raises the possibility that induction of tolerance to a single alloantigen could serve to regulate the immune response to an allograft carrying several MHC and minor antigen differences.