New therapeutic alternatives are needed for patients with progressive RA unresponsive to gold or D-penicillamine. Azathioprine and cyclophosphamide can be effective but have been linked with the development of lymphoreticular malignancies. In an effort to exploit a less toxic agent, we have been impressed by the results and minimal toxicity of low dose oral MTX. Extensive application of this regimen in psoriasis and psoriatic arthritis indicates that low dose MTX does not have an unusual risk for developing cancer. In addition, prior experience with other rheumatic disorders and preliminary studies on the mechanism of action suggest a potential value in RA. We present our initial retrospective results in 28 patients with refractory RA given low dose oral MTX over the past 2.5 yr. An apparent positive response was noted in 19 of these patients (67%) and is similar to the experience of other clinicians. At the same time, the toxicity has been low and, with one exception, amenable to dose modification. Methotrexate in various regimens is being increasingly employed in refractory RA. Issues concerning the pharmacology and potential toxicity are, therefore, important. These topics are reviewed with emphasis on low dose therapy and hepatotoxicity. Despite the encouraging preliminary results it is unclear whether MTX can prevent erosions or improve long-term function and quality of life in RA. There are still no controlled perspective studies comparing MTX to placebo or other immunosuppressive agents in RA. Although short-term toxicity is low, long-term toxicity, especially hepatic, is uncertain. As a result, a controlled, long-term prospective study is necessary.