Methotrexate (MTX) is known as a first-line synthetic disease-modifying anti-rheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). Although the risk of LPD development increases by RA inflammation itself, observation of spontaneous regression of LPD after MTX discontinuation lead to the theory of lymphomagenic role of MTX. In this review, we focused on the several immune response involved in LPD that developed under MTX administration in RA patients.