Introduction: Long-term insulin independence after islet of Langerhans transplantation is rarely achieved. Here, we report a type 1 diabetic patient who received a pancreatic islet transplantation pooled from two donors with respectively one and five HLA mismatches and who died of a cerebral hemorrhage after >13 years insulin independence. The patient remained insulin-free, with normal glycated hemoglobin (5.7%) and basal C-peptide levels of 778ng/mL at the time of her death. The patient was on chronic immunosuppression, associating ciclosporin A, mycophenolate mofetil and low-dose steroids. Material and methods: We performed an histological and immunological analysis of islets transplanted in the liver and of native islets in the pancreas, aiming to study the features of long-term insulin independence. Herein, we assessed the distribution, size and vascularization of insulin positive islets by two-, three-dimensional analysis and optical projection tomography. Moreover, we characterized the different leukocyte subsets including CD68, CD4, CD8, IL-17, Foxp3 and CD20 positive cells in the portal spaces with or without islets. Finally, the donor origins of the islets were identified within the liver by islet microdissection and two-stage nested PCR amplification based on HLA-DRB1 incompatibilities. Results: Importantly, insulin positive islets were absent in the pancreas, ruling out a possible involvement of native b-cell regeneration in endogenous insulin secretion. Insulin positive cells were found throughout the right and left liver. Remarkably few α-cells (β-cell:α-cell ratio was 89:11) could be seen in the intra-hepatic islets. Morphologic changes have occurred over the years within the transplanted islets as suggested by a slightly smaller size (mean diameter: 136μm). 3-D analysis of liver fragments revealed that islets had in fact implanted as unfolded epithelial bands of 39 mm thickness. CD34 analysis revealed that only exceptional vascular channels penetrate into the core of the epithelial band of the transplanted islets suggesting that donor islets depended on peripheral neo-vasculature coming from the recipient. Leukocyte phenotyping showed no evidence of a tolerogenic environment in the islet-containing portal spaces. Finally, HLA typing of microdissected islets showed HLA from the best matched donor in all 23 microdissection samples, as compared to 1/23 for the least matched donor, suggesting that rejection had been prevalent over autoimmunity in this patient. Conclusion: Overall, this case study demonstrates the unique features of allogeneic islets surviving within the liver for several years while maintaining insulin independence.