Multiple streptozotocin (STZ)-induced diabetes in mice and Bio-Breeding/Worcester (BB/W) rats has been employed as a model of human Type I diabetes and cyclosporin (CYA) was reported to prevent diabetes in the BB/W rat. We have investigated whether or not the effect of CYA on multiple STZ-induced diabetes is the same in mice. Male CD-1 mice were given 4 successive daily doses of STZ 40 mg/kg and an additonal dose of 40 mg/kg one week later. CYA treatment at a dose of 10 mg/kg per day or more, was begun on the same day as the STZ treatment and continued for 14 days. Animals received CYA orally which was dissolved in alcohol and Tween 20. Intraperitoneal glucose tolerance tests were done 2, 4 and 8 weeks later. After the last glucose tolerance test, histological examination of pancreatic islets was performed. The blood glucose level after STZ with/without CYA administration resulted in a stepwise increase with time. A significant enhancement of the blood glucose level by CYA was obtained in a dose-dependent manner. The fasting blood glucose levels 2 weeks after the administration of STZ, STZ with CYA (10 mg/kg) and STZ with CYA (30 mg/kg) were 128±39mg/dl, 134±43mg/dl and 325±93mg/dl, respectively. Histologically, at this stage, insulitis was observed in the STZ+CYA group as in the STZ only group. However, alcohol and Tween 20 without CYA caused no change in blood glucose level and histological findings. Pancreatic islets in STZ with/without CYA-treated mice 8 weeks after were small in size and reduced in number as compared with those in the control mice. The present study indicates that CYA has a dose-dependent diabetogenic effect on multiple STZinduced diabetes in mice.