In order to evaluate the role of antiidiotypic antibodies to anti-MHC in human liver transplant recipients, serial serum samples obtained from 10 liver recipients both pre- and posttransplantation were analyzed for the development of HLA alloantisera inhibitory activity by a microcytotoxicity inhibition assay. Seven of the 10 recipients developed strong anti-anti-HLA activity during the immediate posttransplant period, which was able to block killing of a specific alloantiserum to class I MHC antigens (44-100%). Recipients' sera were also able to block class II alloantisera (HLA-DR8) cytotoxicity of B-lymphocytes. The inhibitory activity developed 10-15 days posttransplantation, was cyclical, and was present in the immunoglobulin fraction of the serum. One patient developed specific antibodies to anti-HLA-B7 and had no inhibition for alloantisera to HLA-B8,B17,B49 and B13. Another developed antibodies capable of blocking anti-HLA B44 (mismatched donor antigen) and also cytotoxicity of HLA-B17,B49 (crossreactive group), but showed no significant inhibition of HLA-B13,B8 and B7. One recipient, transplanted across strong (1:500 titer) antilymphocyte crossmatch, rejected the graft within 1 month and failed to develop any inhibitory antibodies to anti-HLA. Two other patients who lost their grafts within 2 months posttransplantation developed only minimal (11% and 16%) and transient inhibition. Immunoprecipitation of surface-labeled, mixed lymphocyte culture stimulated lymphocytes, with sera containing inhibitory antibodies, identified membrane components of approximate molecular weights of 54,43 and 17,000, suggesting T cell clonotypic structures. Thus, these studies provide support for the development of antiidiotypic antibodies to anti-MHC in human liver transplant recipients, which may play a regulatory role in the tolerance of allograft.