Activation of peripheral immune cells leads to increases of interleukin-1beta (IL-1beta) mRNA, immunoreactivity, and protein levels in brain and pituitary. Furthermore, IL-1beta in brain plays a role in mediating many of the behavioral, physiological, and endocrine adjustments induced by immune activation. A similarity between the consequences of immune activation and exposure to stressors has often been noted, but the potential relationship between stress and brain IL-1beta has received very little attention. A prior report indicated that exposure to inescapable tailshocks (IS) raised levels of brain IL-1beta protein 2 h after IS, but only in adrenalectomized (and basal corticosterone replaced) subjects. The studies reported here explore this issue in more detail. A more careful examination revealed that IL-1beta protein levels in hypothalamus were elevated by IS in intact subjects, although adrenalectomy, ADX (with basal corticosterone replacement) exaggerated this effect. IL-1beta protein increases were already present immediately after the stress session, both in the hypothalamus and in other brain regions in adrenalectomized subjects, and no longer present 24 h later. Furthermore, IS elevated levels of IL-1beta protein in the pituitary, and did so in both intact and adrenalectomized subjects. IS also produced increased blood levels of IL-1beta, but only in adrenalectomized subjects. Finally, the administration of corticosterone in an amount that led to blood levels in adrenalectomized subjects that match those produced by IS, inhibited the IS-induced rise in IL-1beta in hypothalamus and pituitary, but not in other brain regions or blood.