Methotrexate (MTX) is the most frequently used drug in the treatment of rheumatoid arthritis. Oral administration has long been the standard way of administration. Generally it is well tolerated adverse some side effects (gastrointestinal) may lead to discontinuation of therapy. A significant lower bioavailability could be observed when MTX was administered orally while the bioavailability after subcutaneous application was similar to the intramuscular treatment. In some patients who did not tolerate or showed no significant clinical improvement under oral MTX, suppression of disease activity could be seen after switching to subcutaneous MTX. The subcutaneous injection is the only parenteral form which can easily be administered at home.