Synthetic peptides corresponding to linear sequences of HLA class I and class II molecules can potently inhibit T lymphocytes responses both in vitro and in vivo. The class I and class II peptides studied to date seem to function by different mechanisms. Nevertheless, several different peptides have been shown to potently induce T cell anergy. Opelz and Terasaki first demonstrated that blood transfusions improved graft survival in transplant patients (19). Data from several sources indicate that blood transfusions are immunosuppressive in: 1) increasing infections in trauma patients who have received transfusions (20), 2) increasing metastases and/or relapses in cancer patients who have been transfused (21), and 3) remissions of autoimmune diseases associated with pregnancy and/or transfusion (22). It is likely that the active constituent of blood transfusions is soluble HLA molecule (23,24). Liver transplants, which are profoundly immunosuppressive in themselves, produce large amounts of soluble HLA (25). Both B and T lymphocytes in culture secrete soluble HLA (26). We hypothesize that soluble HLA is a natural immunoregulatory molecule involved in dampening of the immune response, but, even if this is not the case, synthetic peptides corresponding to HLA sequences have profound effects on T lymphocytes and may prove to be effective for the induction of clinical tolerance in transplant patients.