The transfer of genes encoding immunomodulatory agents into allografts holds promise as an inductive therapy in transplantation (reviewed in refs. 1–3). This approach is clinically applicable, since vascularized transplants are routinely perfused at the time of organ harvest and therefore may be transfected by perfusion. However, many fundamental aspects of this technology must be addressed before it may be optimally applied to clinical transplantation. For example, it has been suggested that immunosuppressive gene therapy may provide advantages over conventional immunosuppression (1–3). Notably, gene transfer should allow for the persistent, local release of the agent within the microenvironment of the graft, thereby negating the deleterious side effects of systemic immunosuppression. Although this feature of immunosuppressive gene transfer is attractive, it has not been validated. Indeed, adenovirus mediated transfer of CTLA4Ig in liver allografts results in readily detectable levels of the transgene product in the sera (4). Hence, local secretion of the transgene product may result in systemic immunosuppression and increased susceptibility to infections and neoplasia. This fundamental aspect of immunosuppressive gene therapy has not been fully addressed and should be rigorously investigated.