Methotrexate is still a mainstay of rheumatoid arthritis treatment, but a significant variability in drug response is observed among patients. It has been proposed that C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase (MTHFR), an enzyme involved in the folate pathway, could be related to its efficacy and toxicity. Many studies have investigated the predictive value of such polymorphisms for Methotrexate outcome, though with discordant results. Our experience on 79 patients did not find any significant association between genotype and drug response and the review of the literature did not provide sufficient evidences to support the use of MTHFR genetic screening in clinical practice.