Methotrexate (MTX), an antifolate, is an anchor drug for the treatment of rheumatoid arthritis (RA). Both folic acid (FA) and folinic acid (FLN) supplements have been shown to reduce the toxicity of MTX when used in RA therapy. The effect of folate supplementation on MTX efficacy still needs to be studied. FA supplementation has been found to have a beneficial effect on homocysteine (hcy) metabolism and may prevent the formation of the less effective metabolite 7-hydroxy-MTX. The cost of FA supplements is substantially less than the cost of FLN supplements. This article reviews clinical trials related to folate supplementation during MTX therapy for RA.