BACKGROUND: The aim of this study was to characterize the immune response against intra-bone marrow (BM-Tx) or intra-liver (Liver-Tx) transplanted islets in the presence or in the absence of immunosuppression. METHODS: Less (C57BL/6 in Balb/c) and highly (Balb/c in C57BL/6) stringent MHC fully-mismatched mouse models were used to evaluate the alloimmune response. Single antigen-mismatched mouse model (C57BL/6 RIP-GP in C57BL/6) was used to evaluate the antigen-specific immune response. Mice received tacrolimus (FK-506, 0.1 mg/kg per day)/mycophenolate mofetil (MMF, 60 mg/kg per day) and anti-CD3 (50 μg/ day) either alone or in combination. RESULTS: Transplant site did not impact the timing nor the kinetics of the alloimmune and single antigen-specific memory T cell responses in the absence of immunosuppression or in the presence of MMF/FK-506 combination. On the other hand, the median time to graft rejection was 28±5.2 and 16±2.6 days (p=0.14) in the presence of anti-CD3 treatment, 50±12.5 and 10±1.3 days (p=0.003) in the presence of anti-CD3/MMF/FK-506 treatment for Liver-Tx and BM-Tx, respectively. Anti-CD3 did not differentially reach BM and liver tissues but was more effective in reducing graft associated T cell responses in Liver-Tx than in BM-Tx. CONCLUSIONS: Islets infused in the BM appear less protected from the adaptive immune response in the presence of the anti-CD3 treatment. This result raises some concerns over the potential of the BM as a site for islet allotransplantation. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.