To evaluate the effectiveness of etanercept in patients with systemic juvenile idiopathic arthritis (SJIA) refractory to methotrexate (MTX) therapy in a pediatric rheumatology practice.Fifteen patients with SJIA with active polyarthritis refractory to higher dose MTX (> or = 20 mg/m2/week) for at least 3 months were included. Patients received etanercept 0.4 mg/Kg twice weekly concomitantly with MTX. Observed period of treatment ranged from 5 to 12 months (median 9 months).Improvement of ESR, swollen and limited joint counts, functional capacity, and general wellbeing was achieved by 14/15 patients. The most significant impact on these variables was observed 3 to 5 months after treatment onset. Mean time to improvement was 2 months. In the 4 patients who presented fever and rash, these signs disappeared after the beginning of etanercept treatment and reappeared during flares. Three patients showed sustained clinical and biochemical remission on low dose MTX (< or = 5 mg/m2/week). Thirteen relapses were observed in 9 (60%) patients at a mean of 7.6 months after therapy was begun. Etanercept was discontinued due to lack of efficacy in 7 patients, only after higher dose (1 mg/kg/dose) was used. MTX and corticosteroid doses were decreased during the observation period. No serious side effects were observed.Etanercept, in combination with MTX, demonstrated benefit soon after initiation of treatment in patients with refractory SJIA, but flares and progressive loss of effectiveness were observed with continued treatment in most patients. Sharp decreases in the dose of MTX and corticosteroids may have contributed to subsequent occurrence of flares. Changes in MTX and corticosteroids doses should probably need to be made gradually, and it is possible that patients on SJIA should continue on therapeutic doses of MTX while being on etanercept in order to maintain therapeutic benefit.