BACKGROUND: The identification of pathway(s) playing a pivotal role in peritransplant detrimental inflammatory events represents the crucial step towards a better management and outcome of pancreatic islet transplanted patients. Recently, we candidate the CXCR1/2 inhibition as a relevant strategy in enhancing pancreatic islet survival after transplantation. METHODS: Here, the most clinically used antiinflammatory compounds (IL1-receptor antagonist, steroids and TNF-α inhibitor) alone or in combination with a CXCR1/2 inhibitor were evaluated in their ability to improve engraftment or delay graft rejection. To rule out bias related to transplantation site, we used well-established preclinical syngeneic (250 C57BL/6 equivalent islets in C57BL/6) and allogeneic (400 Balb/c equivalent islets in C57BL6) intrahepatic islet transplantation platforms. RESULTS: In mice, we confirmed that targeting the CXCR1/2 pathway is crucial in preserving islet function and improving engraftment. In the allogeneic setting, CXCR1/2 inhibitor alone could reduce the overall recruitment of transplant-induced leukocytes and significantly prolong the time to graft rejection both as single agent and in combination with immunosuppression. No other antiinflammatory compounds tested (IL1-receptor antagonist, steroids and TNF-α inhibitor) alone or in combination with CXCR1/2 inhibitor, improve islet engraftment and significantly delay graft rejection in the presence of MMF+FK-506 immunosuppressive treatment. CONCLUSIONS: These findings indicate that only the CXCR1/2-mediated axis plays a crucial role in controlling the islet damage and should be a target for intervention to improve the efficiency of islet transplantation.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.