Since joint destruction, the most important problem in rheumatoid arthritis (RA) , progress rapidly at the onset of the disease, initial treatment using appropriate disease-modifying anti-rheumatic drug DMARD such as methotrexate (MTX) is strongly recommended in order to retard progression of joint damage. However, not a few patients are resistant to MTX and/or intolerant of MTX. Oral tacrolimus 1.5-3 mg/day, an immunosuppressive drug, was approved in Japan for the treatment of RA insufficient to other DMARD. The properties of tacrolimus have the much potential of inhibition of T cell activation, suppressing the production of pro-inflammatory cytokines, improvement of joint inflammation, retarding bone and cartilage destruction, overcoming drug-resistance and so on and, thereby, tacrolimus can be the best alternative to MTX and biologics in RA patients who are refractory to or intolerant of these other drugs.