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The surface modification of islets using poly(ethylene glycol) (PEG) is being studied as a means of preventing host immune responses against transplanted islets. In this study, to completely shield islets with PEG molecules, we increased the amount of PEG conjugated to islet surfaces, by multiple PEGylation or amplified PEGylation using poly-L-lysine, poly(allylamine), or poly(ethyleneimine), respectively. Amplified PEGylation was associated with islet cytotoxicity and functional impairment, but multiple PEGylation affected neither islet viability nor functionality. In addition, when triply PEGylated islets were allotransplanted into diabetic recipients, these islets survived in 3 of the 7 recipients for more than 100 days without any immunosuppressive treatment. Moreover, the blood glucose levels of these 3 recipients were stable and in the normal range. Immunohistochemical analysis showed that 3 of 7 triply PEGylated islets transplants survived for 100 days and that 4 that were rejected before day 20 were all immunologically protected from immune cells. However, unmodified islets were completely destroyed within 1 week. Consequently, we suggest that multiple PEGylation offers an effective means of reducing the immunogenicity of transplanted islets by increasing the amount of surface-bound PEG.