Cyclosporine (CyA) is toxic to the function of isolated islets and this toxicity may, in part, explain the failure of islet allografts as well as autografts with CyA immunosuppression. Not only do canine allografts fail despite CyA immunosuppression, but control autografts given CyA from the day prior to transplantation have a very high failure rate. In this study, we investigated CyA effects on established islet autografts. Twenty mongrel dogs underwent total pancreatectomy and successful intrasplenic islet autotransplantation. Ten served as control autografts (Group 1); five were started on oral CyA on the 5th postoperative day (Group 2) and 5 dogs were given CyA from the 10th day after grafting (Group 3). Intravenous glucose tolerance tests were performed before operation, before starting CyA and after 3 weeks. Plasma insulin was determined by radioimmunoassay. Control dogs remained normoglycemic throughout the study as did Group 3 animals. In Group 2, 2 of 5 dogs failed, both on the 4th day of CyA, while the other 3 were normoglycemic throughout the study. No significant difference was shown among the K values, fasting blood glucose and peak plasma insulin values following IVGTT before and after treatment with CyA. CyA begun the day before autografting gravely compromises graft success. However, after the graft is well established, an adverse effect of CyA on islet cell function is not evident.