Background <p>To summarize the available literature on the management of immunosuppressive therapy in palliative care patients at the end-of-life stage, highlighting challenges associated with decision-making in this context and the current lack of clear clinical guidelines.</p> Methods <p>A systematic search was conducted in the PubMed, EMBASE, and Medline databases for studies evaluating the application of immunosuppressive therapy in patients nearing the end of life or patients who have allograft failure without plans for retransplantation and thus are candidates for palliative care. The search strategy followed PRISMA guidelines.</p> Results <p>We screened 2892 studies, assessed 23 records for eligibility, and included 9 publications in the systematic review. These studies cover different immunosuppressive strategies in palliative care for patients with solid organ or stem cell transplants. The evidence suggests that it is common practice to discontinue immunosuppression for patients with allograft failure who do not have any plans for retransplantation. Corticosteroids can be used to ameliorate the negative effects that arise from immunosuppressant discontinuation.</p> Conclusions <p>The management of immunosuppression after allograft failure requires a careful balance between minimizing drug-related risks and preserving future transplant eligibility. Discontinuing immunosuppression may be appropriate for many patients nearing the end of life, provided that symptom management and ethical considerations are prioritized. Standardized guidelines and multidisciplinary approaches are needed to optimize immunosuppression withdrawal, reduce complications, and ensure patient-centered care.</p>