IL-15 has recently been detected in the synovium of patients with rheumatoid arthritis. IL-15-activated T cells induce significant TNF-α synthesis by macrophages via a cell contact-dependent mechanism, suggesting a key regulatory role for IL-15. Here, we report that the administration of a soluble fragment of IL-15Rα into DBA/1 mice, profoundly suppressed the development of collagen-induced arthritis. This was accompanied in vitro by marked reductions in Ag-specific proliferation and IFN-γ synthesis by spleen cells from treated mice compared with control mice and in vivo by a significant reduction in serum anti-collagen Ab levels. These data directly demonstrate a pivotal role for IL-15 in the development of inflammatory arthritis and also suggest that antagonists to IL-15 may have therapeutic potential in rheumatic diseases.