Azathioprine-prednisone immunosuppression has proven ineffective in rodent, canine, and human islet transplantation. ALS has demonstrated beneficial effects in rodent islet transplantation, but high dose CsA monotherapy remains the most effective immunosuppressive modality in canine islet allotransplantation. Nephrotoxicity prevents effective utilization of such an approach in human islet transplantation. We have been unable to demonstrate additional benefit from the addition of azathioprine and prednisone to CsA immunosuppression in large animal islet allotransplantation. CsA, azathioprine and prednisone all appear to have the potential for adverse effects variously on islet engraftment, insulin secretion, and/or peripheral insulin activity. The effects of CsA appear to be dose related and may be reversible. Our approach in clinical islet transplantation has been to achieve potent induction immunosuppression with Minnesota antilymphocyte globulin, delayed CsA administration, and ongoing maintenance with low dose triple immunotherapy. Initial results are encouraging.