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Islet transplantation is a promising potential cure that remains hindered by immune rejection. We previously showed that ST8Sia6 expression on tumors reduced immune surveillance and hypothesized that this sialyltransferase could protect \u03b2 cells from autoimmune destruction. Here, we demonstrate that ectopic expression of ST8Sia6 in \u03b2 cells of female nonobese diabetic mice (NOD \u03b2ST) decreased the spontaneous incidence of diabetes by 90% and preserved \u03b2 cell mass. NOD \u03b2ST mice had comparable insulitis at 8 weeks of age that did not progress over time compared with littermate controls. \u03b2 Cell\u2013autoreactive B and T cells were present in NOD \u03b2ST mice, indicating a peripheral rather than central mechanism of immune tolerance. The islets of NOD \u03b2ST mice displayed a dampened type 1 immune response and reduced IL-12p35 expression in dendritic cells compared with those of littermate controls. The peripheral protection persisted even after removal of ST8Sia6 expression at 20 weeks of age, indicating that transient expression was sufficient for establishment of tolerance. 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