It is now generally accepted that CD4⁺CD25⁺ T_reg cells play a major role in the prevention of autoimmunity and pathological immune responses. Their involvement in the pathogenesis of chronic arthritis is controversial, however, and so we examined their role in experimental antigen-induced arthritis in mice. Depletion of CD25-expressing cells in immunized animals before arthritis induction led to increased cellular and humoral immune responses to the inducing antigen (methylated bovine serum albumin; mBSA) and autoantigens, and to an exacerbation of arthritis, as indicated by clinical (knee joint swelling) and histological scores. Transfer of CD4⁺CD25⁺ cells into immunized mice at the time of induction of antigen-induced arthritis decreased the severity of disease but was not able to cure established arthritis. No significant changes in mBSA-specific immune responses were detected. In vivo migration studies showed a preferential accumulation of CD4⁺CD25⁺ cells in the inflamed joint as compared with CD4⁺CD25^- cells. These data imply a significant role for CD4⁺CD25⁺ T_reg cells in the control of chronic arthritis. However, transferred T_reg cells appear to be unable to counteract established acute or chronic inflammation. This is of considerable importance for the timing of T_reg cell transfer in potential therapeutic applications.