The major cause of primary nonfunction of transplanted islets is nonspecific inflammation associated with the transplantation procedures. Using mouse islet isografts, we attempted to prevent graft loss mediated by nonspecific inflammation using recipient treatment with nicotinamide (NA) and 15-deoxyspergualin (DSG). Newborn BALB/c islets, ranging in numbers between 1200 and 1500, were transplanted into syngeneic adult mice made diabetic by intravenous injection of 200 mg/kg streptozotocin. Recipient mice were divided into the following four groups, based on the treatment protocol of NA and DSG: intraperitoneal injection (IP) of normal saline (Group 1), IP injection of 2500 mg/kg NA (Group 2), IP injection of 5 mg/kg DSG (Group 3), and IP injection of NA + DSG (Group 4). Treatment started Day -1 and continued until Day 9 (Day 0 is day of transplantation). Blood and urine glucose, body weight, and intravenous glucose tolerance tests (IV-GTT) were examined after transplantation. Reversal of diabetes, as indicated by normoglycemia and negative urine glucose, was higher in Groups 2 (75%), 3 (50%), and 4 (85.7%), compared to Group 1 (11.1%). Especially in Group 4, the endocrine function and morphology of grafted islets were well preserved as shown by K values of IV-GTT and histological studies. These results suggest the importance of islet protection from irreversible damage by nonspecific inflammation at earlier stages of implantation, and the effectiveness of a short course of treatment with NA and DSG.