With the first demonstration of insulin independence following intraportal islet transplantation into a patient with type 1 diabetes, a new era of clinical islet transplantation will begin. This report provides our initial experience of clinical islet transplantion with a total of nine consecutive portal vein islet trasplants in seven diabetic recipients. The first three transplants were done in nonrenal failure diabetics (NRFI) using 6319±2173 islets/kg body weight with islets processed from single pancreas and cultured for 7 days at 24±C. Prednisone, azathioprine, and cyclosporine were initiated prior to transplant. While all three recipients demonstrated C-peptide function posttransplant, all three rejected their grafts at 2 weeks. Five days of OKT3 treatment failed to recover more than 10% of their rejecting islet grafts. The studies were then shifted to established kidney transplant recipients (EKI) maintaining their basal immunosuppression while adding 7 days of Minnesota antilymphoblast globulin (MALG) to the recipient using islets from single donor pancreas that had been cultured for 7 days at 24±C. There were an average of 6161 ± 911 islets transplanted intraportally into three EKI recipients. All three had C-peptide response from the transplant, but none achieved insulin independence. While the first patient rejected his graft at 2 weeks, two recipients demonstrated long-term islet function up to 10 months posttransplant. Sustacal challenge testing demonstrated C-peptide responsiveness, but in a delayed pattern suggesting insufficient islet mass had been transplanted. The next three kidney transplant recipients received islets from more than one donor pancreas averaging 13,916 ± 556 islets/kg body weight. The first of these was the first to achieve insulin independence from 10 to day 25 posttransplant when she appeared to have a rejection episode. The second and third recipients were retransplanted with islets from multiple donorshaving achieved partial islet function from single pancreas donor. The first patient on triple immunosuppression is demonstrating long-term partial function at 184 days but is not insulin independent. The third patient on prednisone and azathioprine received one half his islets after 7-day culture and the other half after 7-day culture combined with cryopreservation. He is continuing to demonstrate insulin independence for 154 days post-transplant with a glycated hemoglobin value of 5.6%. Sustacal challenge data demonstrate a total stimulated C-peptide response of 155 ρmol/ml at 4 months posttransplant compared with 148±12 ρmol/ml for normal controls (NC) and 425 ρmol/ml for nondiabetic, established kidney transplant recipients on triple immunosuppression. These results demonstrate the feasibility of achieving insulin independence in type 1 patients after islet transplantation and justify continuing these studies to document how many recipients of islet transplantation can achieve insulin independence for what duration posttransplant.