Group A streptococcal cell wall fragments (SCW) induce erosive polyarthritis, characterized by synovial cell hyperplasia and intense mononuclear cell infiltration, in susceptible rats. Because of the known antiproliferative and immunomodulatory effects of interferon (IFN), we evaluated the effect of systemically administered α,β and γ IFN on the evolution of these destructive lesions. Treatment with γIFN not only reduced the acute response, but had an even greater suppressive effect on the chronic mononuclear cell-mediated destructive phase of the disease (articular index 10.2 ± 1.2 for SCW only versus 3.8 ± 0.7 for SCW + γIFN; p < 0.01). Treatment with γIFN was more effective in the suppression of the arthritis than α,βIFN. Histopathologic evaluation of the joints demonstrated that γIFN-treated animals had significantly fewer inflammatory cells, and less synovial hyperplasia and erosions than the SCW controls. γIFN suppression of mononuclear cell prostaglandin synthesis and synovial fibroblast proliferation was consistent with its anti-arthritic effects. These data indicate that the pathophysiology of SCW-induced erosive polyarthritis is subject to regulatory control by γIFN and that the mechanisms of suppression may be relevant in the treatment of rheumatoid arthritis.