Five patients with severe, treatment refractory rheumatoid arthritis were treated with high dose intravenous methotrexate (500mg/m2) followed by leucovorin (50 mg/m2). Four courses of chemotherapy were given over a 2 month interval. At the end of the final course, there are a 50% or greater improvement in joint swelling and pain indices and morning stiffness in all patients. Clinical responses persisted for 6 to 14 weeks post therapy. High dose methotrexate-leucovorin was associated with a significant reduction in DR antigen expression on peripheral Leu 2, Leu 3 and Leu 4 lymphocytes.