Tumor necrosis factor (TNF) is a major proinflammatory cytokine in the rheumatoid joint. TNF activity can be neutralized by administration of a recombinant version of its soluble p75 TNF receptor linked to the Fc portion of human immunoglobulin IgG1 (etanercept). The present study examined the combination of etanercept with methotrexate (MTX) in a group of patients with rheumatoid arthritis (RA) who had persistent activity despite monotherapy with MTX. The etanercept-MTX group had a significantly better outcome than the placebo-MTX group using American College of Rheumatology (ACR) criteria. At 6 months, 71% of the patients in the etanercept-MTX group had an ACR 20% response (versus 27% in the placebo-MTX group). In the etanercept-MTX group, 39% had an ACR 50% response (versus 3% in the placebo-MTX group), and 15% in the etanercept-MTX group versus 0% in the placebo-MTX group met the robust ACR 70% response. The present study indicates that etanercept is a novel and robust drug in combination with MTX for the treatment of RA.