Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disorder in children. Although methotrexate (MTX) is the first line disease-modifying antirheumatic drug for JIA, many patients do not respond well or cannot tolerate MTX. The aim of this study was to compare the effect of combination therapy of MTX and leflunomide (LFN) with MTX in patients who do not respond to MTX. Eighteen patients (2-20 years old) with polyarticular, oligoarticular or extended oligoarticular subtypes of JIA who did not respond to conventional JIA therapy participated in this double-blind, placebo-controlled, randomized trial. The intervention group received LFN and MTX for 3 months while the control group received oral placebo and MTX at a similar dose to the intervention group. Response to treatment was assessed every 4 weeks using the American College of Rheumatology Pediatric criteria (ACRPed) scale. Clinical criteria, including number of active joints and restricted joints, physician and patient global assessment, Childhood Health Assessment Questionnaire (CHAQ38) score, and serum erythrocyte sedimentation ratelevel, did not differ significantly between groups at baseline and at the end of the 4th and 8th weeks of treatment. Only the CHAQ38 score was significantly higher in the intervention group at the end of the 12th week of treatment. Analysis of the effect of treatment on study parameters revealed that only the global patient assessment score differed significantly between groups (p = 0.003). The results of this study showed that combining LFN with MTX does not improve clinical outcomes of JIA and may increase side effects in patients who do not respond to MTX.