Introduction: The complement system, an integral part of innate immunity, includes over 60 proteins and can be activated through three pathways: classical, lectin, and alternative. Uncontrolled complement activation can lead to complications in allo- and xenotransplantation, including graft rejection. Transgenic expression of human complement regulatory proteins in donor organs has been used to mitigate these issues, but challenges still remain. Here, we aim to summarize current literature supporting the role of complement inhibition in preserving graft function in xenotransplantation. We also examine clinical experiences with C3/C3b-targeted complement inhibition with pegcetacoplan in post allotransplantation complications such as antibody-mediated rejection (AMR), thrombotic microangiopathy (TMA) and C3 glomerulopathy and extrapolate these findings to xenotransplantation. Furthermore, we explore the mechanistic differences among clinically approved complement inhibitors and discuss their potential integration into immunosuppressive regimens for xenotransplantation.
Methods: A literature review from 2000 to 2025 was conducted, focusing on complement activation in donor organ injury and rejection processes. 
Results: All complement pathways contribute to xenotransplantation-related injury.  For example, ischemia reperfusion injury (IRI) can activate all pathways, while preformed or de novo anti-pig antibodies can trigger the classical pathway. Complement activation has been documented across various xenograft types and is a key driver of hyperacute rejection. Despite reducing hyperacute rejection with the introduction of human complement regulatory transgenes, residual complement activity still causes inflammation and ultimately lead to graft rejection. Emerging evidence underscores the critical role of complement activation in post-transplant complications such as graft rejection, mediated through mechanisms such as IRI, TMA, AMR as well as cell-mediated transplant rejection. 
Conclusions: Clinical experience with complement-targeted therapies in allotransplantation  showed promising efficacy. With the availability of multitude of approved inhibitors targeting various components of the complement cascade, there is an opportunity to tailor therapeutic approaches to block specific pathways relevant to xenograft rejection. Incorporating complement inhibitors into immunosuppressive protocols may provide a more comprehensive approach to immune modulation, thereby improving xenograft outcomes. As an example, pegcetacoplan has recently been used in animal xenotransplantation models, decedent models and living recipients with promising signs of efficacy. Future studies should focus on optimizing the timing, dosage, and combination of complement inhibitors to maximize their protective effects in the xenotransplantation setting.