The objective of this study was to analyze the impact of rapamycin and/or cyclosporine on the metabolic efficiency of intrasplenic islet autografts in dogs. An insulin modified frequently sampled intravenous glucose tolerance test was carried out before, on the last of 30 days treatment with drug and 30 days after cessation of drug therapy in dogs with stable function 1 to 7 years after total pancreatectomy and intrasplenic islet autografting. Analyses were performed for glucose clearance, insulin release, insulin sensitivity, and other variables. Rapamycin treatment was associated with increased glucose clearance, increased total and stimulated insulin release in response to glucose, and increased fasting plasma insulin level, as well as reduced insulin clearance. Cyclosporine at 300 micrograms/L had little impact on the measured variables. Treatment with rapamycin and cyclosporine showed a similar (although less-marked) pattern of changes to rapamycin alone. Rapamycin, with or without concomitant cyclosporine, was not associated with adverse impact on islet function or glucose metabolism in this canine model of pancreatic islet transplantation.