It has been suggested that pancreaticβ-cell destruction occurring during the process leading to insulin-dependent diabetes mellitus (1DDM) involves formation of nitric oxide (NO). We have presently studied the effect of aminoguanidine (AG), which has recently been reported to inhibit generation of NO induced by the cytokine interleukin-1β. AG currently counteracted IL-1βinduced impairment of the glucose oxidation rate in rat pancreatic islets. Then we studied the effect of AG on the development of hyperglycemia and pancreatic insulitis in mice treated with multiple low dose injections of streptozotocin (40 mg/kg body-weight for five consecutive days). It was found that one daily intraperitoneal injection of AG (50 mg/kg body-weight) for 14 days failed to prevent the development of diabetes as well as insulitis following the streptozotocin injections. Furthermore, the mice treated with streptozotocin plus AG showed an increased mortality compared to mice treated with streptozotozin plus saline. Although the present data do not exclude a role for NO in IDDM, it raises concerns about the use of testing AG as therapeutic agent in IDDM.