Etanercept (Enbrel™) has specifically been developed to achieve therapeutic neutralization of TNF. DNA encoding the soluble portion of the human p75 TNFR was linked to DNA encoding the Fc portion of the human IgG molecules and expressed in a mammalian cell line. The resultant protein binds two TNF molecules and has increased circulating half-life due to the Fc moiety. In the first placebo-controlled trial, 75% of patients receiving the highest dose of etanercept (16 mg/m2 subcutaneously twice a week) achieved at least a 20% ACR clinical response after 3 months of therapy. This improvement was associated with significant reductions in pain and morning stiffness, as well as in the biochemical markers (ESR and CRP) of disease activity. In a subsequent placebo-controlled phase III study, using a dosing schedule of 10mg or 25mg of etanercept subcutaneously biweekly, sustained clinical efficacy and safety were both verified over a period of 3 months. The 25-mg dose proved superior to the 10-mg dose in terms of effectiveness. No adverse events other than injection site reactions were more commonly noted with either dosage compared to the placebo group. Rheumatoid arthritis (RA) patients with suboptimal clinical responses on DMARD therapy may be the most optimal candidates for the addition of the TNF antagonist etanercept to the treatment regimen. Results of a phase II/III study of combination therapy with etanercept and methotrexate in RA patients refractory to moderate doses of methotrexate have recently been reported. The combination of etanercept and methotrexate resulted in 71% of patients achieving a 20% ACR response, compared with only 27% of patients who received methotrexate alone. The encouraging clinical results observed in short-term trials using etanercept clearly warrant further studies to determine whether TNF inhibitors are capable of modifying the destructive component of the disease and to assess safety in long-term use. A pivotal trial with etanercept is now in progress comparing etanercept with methotrexate in early RA. Radiographic changes will be measured in this trial.