GLUCOCORTICOID hormones are important for vital functions and act to modulate inflammatory and immune responses^1,2. Yet, in contrast to other hormonal systems, no endogenous mediators have been identified that can directly counter-regulate their potent anti-inflammatory and immunosuppressive properties. Recent investigations of the protein macrophage migration inhibitory factor (MIF), which was discovered originally to be a T-lymphocyte-derived factor^3,4, have established it to be a pro-inflammatory pituitary and macrophage cytokine and a critical mediator of septic shock^5–7. Here we report the unexpected finding that low con-centrations of glucocorticoids induce rather than inhibit MIF production from macrophages. MIF then acts to override gluco-corticoid-mediated inhibition of cytokine secretion by lipopoly-saccharide (LPS)-stimulated monocytes and to overcome glucocorticoid protection against lethal endotoxaemia. These observations identify a unique counter-regulatory system that functions to control inflammatory and immune responses.