IGF-II has been reported to decrease neonatal islet cell apoptosis and in vitro adult islet cell necrosis and apoptosis, but the usefulness of IGF-II in a transplantation setting is unknown. We evaluated the effect of in vitro IGF-II incubations on microencapsulated rat islet survival both in vitro and in minimal mass transplantations into diabetic mice. After 6 d in culture, fresh examinations, histology, fluorescence microscopy, sodium 3'-[1-(phenyl-amino-carbonyl)-3,4-tetrazolium]-bis (4-methoxy-6-nitro)-benzene sulfonic acid hydrate assay, and apoptosis studies all indicated that IGF-II significantly improves islet cell viability in a dose-dependent fashion. IGF-II 100 ng/ml and 500 ng/ml induced a 51% and 83% increase of viable islets (P = 0.052, P < 0.01). A 20%, 29%, and 33% reduction of the apoptotic index was observed with 50, 100, and 500 ng/ml incubations respectively (P < 0.05; P < 0.005; P < 0.001). Ten weeks after transplantation of 150 encapsulated rat islet equivalents incubated with IGF-II 500 ng/ml, 80% of diabetic mice were normoglycemic. Without IGF-II preincubation, only 8% of the recipients remained normoglycemic with the transplantation of 150 islets and 42% with 300 islets (P < 0.05). In conclusion, IGF-II promotes islet cell survival, and allows successful transplantation using a smaller number of islets.