Intra-articular injection of cell walls from the gram-positive bacterium Streptococcus pyogenes induces an arthritis in both streptococcal cell wall (SCW)-primed and naive mice. This joint inflammation subsides after 2 weeks but it could be reactivated by systemic injection of SCW in a dose-dependent way. The primary arthritis as well as the flare-up reaction were more vehement in immunized than naive mice. Pretreatment with antilymphocyte serum of nonimmunized arthritic mice before systemic challenge completely inhibits the flare-up reaction, suggesting the involvement of lymphocytes in the reactivation. Dose-response studies showed that intravenous challenge with SCW amounts too small to induce a primary arthritis were able to reactivate a chronic arthritis, implying that an inflamed joint is in a hyperreactive state, probably due to locally retained lymphocytes. Arthritis as a result of injection with SCW can be reactivated by fragments of a nonrelated, gram negative endogenous bacterium, Escherichia coli. The latter finding might be of importance for the understanding of the pathogenesis of chronic arthritis: once an arthritis is induced by one bacterium, other (unrelated) bacteria, probably derived from an endogenous source, may be able to reactivate the inflammatory process, thus contributing to chronicity.