The monokines interleukin-1α and -β have been implicated as effector molecules in the immune-mediated pancreatic beta-cell destruction leading to insulin-dependent diabetes mellitus. Here we investigated the effects of interleukin-1 receptor antagonism on insulin and glucagon release of rat, mouse and human islets exposed to recombinant human interleukin-1β, and on interleukin-1β induced changes in blood glucose, serum insulin and serum glucagon levels in Wistar Kyoto rats. The interleukin-1 receptor antagonist reduced the co-mitogenic effect of interleukin-1β on mouse and rat thymocytes with a 50% inhibitory concentration of 10- and 100-fold molar excess, respectively. Complete inhibition was obtained with a 100–1,000-fold molar excess. However, at a 100-fold molar excess the interleukin-1 receptor antagonist did not antagonise the potentiating effect of interleukin-1βon rat islet insulin accumulation during 3 and 6 h of exposure or of interleukin-1β-induced inhibition of insulin release after 24 h. In contrast, interleukin-1β-stimulated islet glucagon release was completely antagonised by a 100-fold molar excess of interleukin-1 receptor antagonist. A 10,000-fold molar excess of interleukin-1 receptor antagonist was needed to antagonise interleukin-1β stimulatory and inhibitory effects on rat beta-cell function in vitro. A 100-fold excess of interleukin-1 receptor antagonist could not counteract interleukin-1β effects on mouse and human beta cells, excluding species difference in the efficacy of the human interleukin-1 receptor antagonist. An anti-mouse interleukin-1 receptor type I antibody completely abolished interleukin-1β effects on isolated mouse islets. A 10–100-fold molar excess of interleukin-1 receptor antagonist antagonised interleukin-1β-induced fever, hypercorticosteronaemia and hyperglucagonaemia, but not interleukin-1β-induced reduction in insulin/glucose ratio in normal rats. In conclusion, our results suggest that antagonism of interleukin-1β effects on beta cells requires higher concentrations of interleukin-1 receptor antagonist than those necessary to block interleukin-1 action on islet alpha cells and other interleukin-1 targets in vitro and in vivo. This may contribute to the understanding of the specificity of the immunological beta-cell destruction leading to insulin-dependent diabetes.