We have previously demonstrated that Interleukin‐1 (IL‐1), a cytokine mainly produced by activated monocytes, stimulates the pituitary–adrenal axis and affects glucose homeostasis. Comparative studies revealed that a β form of recombinant human IL‐1, similar to the mature peptide secreted naturally, is more powerful than other preparations of this monokine in stimulating adrenocorticotrophic hormone (ACTH) and corticosteone output. Another monokine, tumor necrosis factor (TNF), does not share with IL‐1 the capacity to induce such effects. In extending out studies to rats, we showed that increased ACTH and blood corticosterone levels are also induced by IL‐1 in this species. Another in vivo activity of IL‐1 relates to its capacity to induce a reduction in blood glucose levels. Our studies strongly suggest that, as opposed to other effects elicited by IL‐1, blockade of prostaglandin synthesis does not effect the capacity of IL‐1 to stimulate insulin output and produce hypoglycemia. Administration of IL‐1 to adrenalectomized mice, which are defective in counterregulatory mechanisms of glucose homeostasis, resulted in marked hypoglycemia. In contrast to the response observed in normal mice, in adrenalectomized animals this effect was paralleled by decreased blood insulin levels. IL‐1 was also injected into alloxan‐diabetic mice. A marked reduction in blood glucose levels occurred in these animals. This effect was already noticeable 1 hr after injection. After 2 hr and for at least another 6 hr, glucose levels of alloxan‐treated mice injected with IL‐1 remained within the normal range. A possible early increase in release of residual insulin in diabetic animals was ruled out. These data, together with previous studies, suggest that IL‐1‐induced hypoglycemia is not only mediated by its insulin secretagogue effect. The fact that IL‐1, a key mediator of immunological and inflammatory reponses, affects crucial mechanisms under control of the central nervous system suggests that it play a major role in neuroendocrine immunoregulation.