Recent evidence from clinical trials of allotransplantation indicated emerging benefits in transplant recipients treated with GLP-1 Receptor Agonists (GLP-1 RA).  GLP-1 RA were associated with better graft and patient survival in kidney transplant recipients with type 2 diabetes. GLP-1 RA were associated with a 49% lower incidence of death-censored graft loss, and 31% lower mortality (The Lancet D&E, May 2025). In another recent report to evaluate the safety and efficacy of GLP-1 RA in kidney transplant recipients indicated that GLP-1 RA treatment was associated with a significant decrease HbA1c and total daily insulin requirements, indicating benefits in improving glycemic control, without altering tacrolimus levels (Clinical Kidney Journal, February 2024). We have previously reported that engraftment and long-term islet graft function improved in recipients treated with GLP-1 RA in addition to standard immunosuppression (IS). We have more recently observed that most islet transplant recipients benefiting from long-term islet graft function, were also assuming GLP-1 RA as adjunct support therapy. GLP-1 RA have been primarily used for the treatment of type 2 diabetes and obesity due to their metabolic effects. However, emerging evidence suggests they may also exert immunomodulatory effects and contribute to immune tolerance, particularly relevant in autoimmune diseases like type 1 diabetes (T1D) and in transplantation settings.  This hypothesis was recently supported by observations in a 36 y/o male recipient of islet allotransplantation treated with standard maintenance IS. The subject remained insulin free for 82 months. After resumption of exogenous insulin treatment, stimulated C-peptide was 4.3 ng/mL and HbA1c 6.5%, and 7 months later DPP-4 inhibitor treatment was added and over time replaced by GLP-1 RA. [DB1] 19 years post-ITx, the subject was diagnosed with COVID-19 and was switched from dulaglutide to semaglutide. Twenty-two years post-islet transplantation, IS was discontinued due to recurrent infections. Prior to IS-discontinuation, HbA1c was 6.9%. Peak stimulated C-peptide 9 months prior was 1.63 ng/mL and seven months after IS-discontinuation was 2.85 ng/mL. Testing for allo-antibodies was negative. Coincidentally with introduction of semaglutide, an increase in Treg:Tconv (regulatory:conventional T cell) ratio was noted in addition to a reduction in the % of CD8 effector memory cells. Stable graft function was maintained post IS-discontinuation with no evidence of allograft rejection. A favorable Treg:Tconv profile and decline in CD8 T effector memory cells were noted following initiation of semaglutide. We hypothesize that chronic GLP-1 RA therapy was associated with an immunomodulatory and tolerance permissive effect that may have facilitated immune adaptation to the islet allograft, preventing rejection following IS-discontinuation. Additional studies are required to further evaluate the potential role of GLP-1 RA in tolerance induction strategies.