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 days in culture, fresh examinations, histology, fluorescence microscopy, XTT 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 pre-incubation, 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.