The effects of T helper lymphocyte and laeel depletien were examined for their ability to independently and synergistically achieve prolongation of xenogeneic (rat-to-mouse) islet transplants. Recipient mice were depleted of T helper lymphocytes by short-term treatment with the anti-L8T4 monoclonal antibody GK1.5. Donor rat islets were treated prior to transplantation with a concentration of anti-la immunotojdn (13.4xRT) that selectively depleted I«' cells within the islets while leaving functional insulin-secreting £-cells unaffected. Anti-L3T4 treatment alone allowed transplants to be prolonged compared with untreated controls; however, all such treated mice rejected their xenogeneic transplant within 22 days. Although 18.4XRT treatment of donor islets alone did not prolong engraftment, when donor rat islets were pretreated with the anti-la immu- notoxin and grafted into LgT4-depleted mice, normo- glycemia was maintained for greater than 50 days in 56% of transplants, These results suggest that neither L8T4 depletion nor anti-la immunotoxin treatment alone is enough to achieve indefinite survival of xeno- geneic islets. However, decreasing the immunogenicity of the transplanted islets by anti-la immunotoxin treatment prior to transplantation into anti-L8T4 treated mice can allow greatly prolonged xenogeneic graft survival.