Intra-articular injection of interleukin-1 (IL-1) into the knee joints of rabbits produces a synovitis associated with the loss of proteoglycan from the matrix of articular cartilage. This experimental finding supports the hypothesis that IL-1 is a possible mediator of the pathology of inflammatory joint diseases and suggests that antagonism of IL-1 could offer a therapeutic approach to these diseases. It has recently been reported that culture of human monocytes on adherent IgG stimulates these cells to synthesize a specific inhibitor of IL-1 bioactivity (IL-1ra) that acts as a receptor antagonist with lymphocytes and mesenchymal cells. We have now shown that intravenous injection of IL-1ra into rabbits given an intra-articular injection of recombinant IL-1 beta not only inhibits the entry of leukocytes into the synovial lining and joint cavity but blocks the ability of IL-1 to cause loss of proteoglycan from articular cartilage. This ability of IL-1ra to inhibit IL-1-induced arthritis in the rabbit reveals that this protein has appropriate pharmacokinetic and pharmacodynamic properties and further strengthens the belief that it may be a useful therapeutic agent.