AbstractTo investigate the role of CD4+cells in the induction and maintenance of streptococcal cell wall (SCW)‐induced arthritis, Lewis rats were treated with a monoclonal antibody against rat CD4 (W3/25). Injection before onset of the arthritis resulted in resistance to SCW arthritis. Treatment with anti‐CD4 during ongoing arthritis induced an amelioration of the arthritis, demonstrating that CD4+cells are involved in both the induction and effector phases of the chronic arthritis.After return of CD4+cells to normal levels in the circulation, no arthritis occurred in protected rats, despite the continued presence of SCW in the body. Even reinjection of SCW could not induce arthritis in these rats, suggesting that tolerance to SCW had occurred. In addition, these tolerized rats were refractory to actively induced adjuvant arthritis (AA), but were susceptible to passively transferred AA.Our data imply, that (a) treatment with anti‐CD4 plus SCW induces a long‐term resistance to SCW‐induced arthritis and adjuvant arthritis, (b) SCW andM. tuberculosismay use similar mechanisms of regulation of arthritis and (c) active peripheral suppression is not the mechanism of this nonrespo