BACKGROUND: Tumor necrosis factor (TNF)-alpha is produced by macrophages and other cells, and is believed to participate in granulomatous inflammation. Targeted antagonism of TNF-alpha has been proposed as a novel treatment strategy for sarcoidosis. Etanercept is a dimeric fusion protein that binds specifically to TNF-alpha, rendering it biologically inactive. OBJECTIVE: To assess whether etanercept has potential efficacy in the treatment of progressive pulmonary sarcoidosis. DESIGN: Prospective, open-label, phase-2 treatment trial. SETTING: Mayo Clinic, Rochester, MN. PATIENTS: Stage II or III progressive pulmonary sarcoidosis. INTERVENTION: Etanercept, 25 mg subcutaneously twice weekly. MEASUREMENTS: Pulmonary function, chest radiographs, dyspnea, and TNF-alpha levels in serum and BAL fluid. RESULTS: The study was terminated after the enrollment of 17 patients due to an early-stop clause of the pretrial study design related to excessive treatment failures. Neither absolute levels of TNF-alpha nor TNF-alpha activity in the serum, BAL fluid, or alveolar macrophages were able to predict which patients would respond to etanercept. CONCLUSIONS: In patients with progressive stage II or III pulmonary sarcoidosis, etanercept was frequently associated with early or late treatment failure. These data would not support the design of a large multicenter randomized trial comparing etanercept with conventional corticosteroid therapy.