Wistar rats were treated daily with cyclizine (50-75 mg kg-1) and autopsied every week until the eighth week of the treatment. Although no evident change could be detected by either serum analysis or by light microscopy from the first week to the fourth week, electron microscopy revealed that beta cells showed depletion of secretory granules and cystic dilation of the rough endoplasmic reticulum from the first week. A significantly higher level of plasma glucose and a lower level of plasma insulin than those of untreated rats were recognized from the fifth week. A diabetic pattern was also observed in the glucose tolerance test which was conducted at the seventh week. From the sixth week, large cytoplasmic vacuoles were observed light microscopically in islet cells. Electron microscopic examination revealed that the vacuoles originated from the rough endoplasmic reticulum in beta cells, while no prominent change was found on the Golgi apparatus. In addition to the above findings, immunocytochemical study with anti-insulin serum demonstrated that the staining intensity of the beta cell cytoplasm became weaker (as judged by light microscopy) from the fifth week, but large cytoplasmic vacuoles were stained positively under both the light microscope (PAP method) and the electron microscope (enzyme-labelled antibody method). These findings suggested that the depletion of secretory granules and accumulation of insulin or its precursor in the rough endoplasmic reticulum occurred in beta cells. The diabetogenic effect of cyclizine on rats is discussed with reference to the immunocytochemical findings.