Anti-CD4 treatment is reported to prevent collagen-induced arthritis if administered before the onset of clinical disease but has relatively little effect on established arthritis. In contrast, we have recently shown that anti-tumor necrosis factor alpha/beta (TNF) treatment reduces the severity of established arthritis. We now study the effect of combined administration of anti-CD4 monoclonal antibody (YTS 191.1.2/YTA 3.1.2) and anti-TNF monoclonal antibody (TN3-19.12) in established arthritis. Anti-CD4 treatment caused some reduction in paw-swelling but did not significantly prevent joint erosion. A suboptimal dose of anti-TNF alone had no significant effect on arthritis. In contrast, anti-CD4 plus suboptimal anti-TNF significantly reduced paw-swelling, limb involvement, and joint erosion. As previously reported, an optimal dose of anti-TNF alone inhibited paw-swelling, limb involvement, and joint erosion. However, optimal anti-TNF combined with anti-CD4 caused significantly greater reductions in paw-swelling and joint erosion than those achieved by optimal anti-TNF alone. Coadministration of anti-CD4 was also effective in preventing an antibody response to the hamster anti-TNF antibody, which may have implications for long-term therapy in human disease. Thus anti-CD4 acts synergistically with anti-TNF in ameliorating established collagen-induced arthritis and this combined therapeutic approach may provide effective long-term control of rheumatoid arthritis.