Rheumatoid arthritis (RA) is a complex, heterogeneous systemic autoimmune disease involving a wide array of joint inflammation and bone erosion, eventually leading to serious disablity. Targeting to key points of the pathogenesis of RA is the current mainstay of new therapeutics development. TRAIL belongs to TNF superfamily, and accumulated evidences suggest TRAIL may be implicated its actual biological function in immune-regulationin besides triggering apoptosis. In this study, we demonstrated that TRAIL significantly inhibited joint inflammation, restored bone erosion and suprressed systemic inflammatory cytokines in an inflammatory arthritis animal model. Interestingly, the suppression of joint inflammation was not due to the TRAIL-mediated induction of apoptosis in T cells, macrophages or synovial fibroblasts. By contrast, TRAIL could directly inhibit T cell proliferation and T cell-derived inflammatory cytokines, indicating TRAIL may exert its anti-arthritic effect through T cell inactivation. Moreover, TRAIL-receptor (TRAIL-R) knockout mice developed more severe disease, and the protective effects of TRAIL were abolished in TRAIL-R knockout mice in the experimental arthritis animal model. Our results provided evidence of a novel mechanism of TRAIL in anti-inflammatory arthritis and shed light on the possible therapeutic application in inflammatory arthritis and in developing better strategies for treating RA in the future.