One major limitation in pancreatic islet transplantation is availability of donor tissue. Donor shortage is exacerbated by islet apoptosis from the stresses of islet isolation and transplantation. Furthermore, the side effects of immunosuppressive drugs preclude transplants into patients whose diabetes is controlled by parenteral insulin. We hypothesised that over-expressing anti-apoptotic Bcl-2 or secretion of immunomodulatory CTLA4Ig molecules in islet beta cells would enhance survival of transplanted islets while minimizing systemic side effects. Over-expression of Bcl-2 neither significantly increased preservation of islet cell mass after transplantation into immunocompromised recipients nor decreased cytokine-mediated apoptosis in vitro. Although Bcl-2 over-expression alone was insufficient in protecting islet allografts from rejection, its beneficence was shown by the enhancement of protection when the adaptive immune response was inhibited by locally produced CTLA4Ig. Thus, the combination of anti-apoptotic and immunosuppressive intervention has additive or synergistic efficacy and may reduce the level of systemic immunosuppression or quantity of donor tissue required.