Several immunosuppressive medications are used simultaneously to protect transplanted islets. However, reports of severe side effects induced by immunosuppressive drugs have prompted attention on developing ways to reduce their toxicities. Toward attenuating the immunogenicity of islets, we studied a combination therapy of PEGylation and cyclosporin A (CsA) as a new immunoprotective strategy. This study aimed to find out whether PEGylation combined with cyclosporine and applied on islet surfaces could bring about a synergistic effect of reducing the dose of immunosuppressive medications as well as enhancing their medical effects. After islets were transplanted into the kidney of diabetic rats, different doses of CsA were administered daily. When 3 mg/kg of CsA was administered for 2 weeks, unmodified islets were completely rejected within 2 weeks, whereas the PEGylated islets survived for 32+/-14.6 days. When 1 mg/kg of CsA was further administered following the initial, 2-week CsA treatment of 3 mg/kg, the PEGylated islets in all recipients survived up to 100 days prior to nephrectomy and also rapidly responded to the fluctuation of blood glucose level. PEGylated islets were also present in large numbers in the transplantation site without causing the infiltration of immune cells. Therefore, these findings suggest that, when combined with an immunosuppressive drug, PEGylation of islets could have a dose reducing effect on the immunosuppressive medication and thus synergistically improve the survival time of islets.