The efficacy of weekly low-dose methotrexate treatment of rheumatoid arthritis is well documented. Efficacy and adverse effects are both dose dependent. and adverse effects rather than lack of efficacy are the main reason for discontinuing therapy. Several adverse effects are related to folate deficiencies, largely due to the antifolate properties of methotrexate. In order to reduce adverse effects without compromising drug efficacy, numerous clinical investigations have been performed using supplementation with folic or folinic acid during methotrexate therapy of patients with rheumatoid arthritis, addressing both the timing of folate supplementation and the weekly folate-to-methotrexate ratio. Based on these studies, an individually adjusted supply of folic acid rather than folinic acid is proposed. For many patients, however, a properly balanced diet is sufficient to avoid folate deficiency.