The aim of this study was to assess the efficiency and safety of the Edmonton immunosuppression protocol in recipients of islet-after-kidney (IAK) grafts. Fifteen islet infusions were administered to 8 patients with type 1 diabetes and a functioning kidney graft. Immunosuppression was switched on the day of transplantation to a regimen associating sirolimus-tacrolimus-daclizumab. Insulin-independence was achieved in all patients for at least 3 months, with an actual rate of 71% at 1 year after transplantation (5 of 7 patients). After 24-month mean follow-up, five have ongoing insulin independence, 11–34 months after transplantation, with normal HbA1c, fructosamine and mean amplitude of glycemic excursions (MAGE) values. Results of arginine-stimulation tests improved over time, mostly after the second islet infusion. Severe adverse events included bleeding after percutaneous portal access (n = 2), severe pneumonia attributed to sirolimus toxicity (n = 1), kidney graft loss after immunosuppression discontinuation (n = 1), reversible humoral kidney rejection (n = 1) and fever of unknown origin (n = 1). These data indicate that the Edmonton approach can be successfully applied to the IAK setting. This procedure is associated with significant side effects and only patients with stable function of the kidney graft should be considered. The net harm versus benefit has not yet been established and will require further studies with larger numbers of enrolled subjects.