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Background and AimRheumatoid arthritis (RA) is a chronic and progressive systemic inflammatory condition, which affects mainly the joint synovial. There is not any definite treatment. The Object of this study was comparison effectiveness of combination leflunomide and Methotrexate to Etanercept. Material and Method A systematic review was performed to evaluate the Effectiveness of LEF + MTX in comparison with ETN. Electronic databases, including Cochrane, Pub Med, Scopus, and CRD were searched up to December 2015. Quality assessment was conducted by the Jadad score and The Cochrane Collaboration’s tools. Meta-analysis was calculated for effective outcomes in the included studies. Effectiveness was measured by ACR. This review was updated up to January 2019.   Results 2780 eligible articles were found in the search. Finally, five studies were eligible for inclusion. Effectiveness outcome showed an improvement in ACR criteria. The difference of improvement in ACR70 , ACR50,  ACR20  criteria in LEF + MTX group in compared with placebo were reported 78 / 0 % , 20 % , 27% and of ETN respectively were 0.003 % , 21.93 % , 32% .   Conclusion Combination of Leflunomide with Methotrexate was effective and it would be an effective combination which can be used before biomedical medication regarding their cost