Graft-versus-host disease (GVHD) is the major complication of allogeneic bone marrow transplantation (BMT). Dysregulation of inflammatory monokines such as tumor necrosis factor alpha (TNF alpha) has been noted in both clinical and experimental GVHD. We present evidence that interleukin-1 (IL-1), another inflammatory monokine, is an important mediator of GVHD. Expression of the gene for IL-1 alpha as well as the gene for TNF alpha is increased in the skin of mice with GVHD. Inhibition of IL-1 function by the in vivo administration of IL-1 receptor antagonist (IL-1ra) reduces the immunosuppression and mortality of GVHD without impairing the engraftment of hematopoietic stem cells. GVHD thus appears to be a systemic inflammatory process in which monokines, especially IL-1, appear to be important mediators. Inhibition of IL-1 by IL-1ra represents a novel approach to the understanding and control of GVHD.