In spite of the increasing use of single and multiple pharmacologic intravenous pulses of MPS for immunosuppression in various diseases, their immunosuppressive effects have not been documented. We treated two groups of six patients with classic RA unresponsive to conventional therapy with either one or three daily 1 gm intravenous doses of MPS and measured the immune response and clinical activity over 16 weeks. Lymphocytopenia with selective T lymphocyte suppression was noted 2 hr following each infusion, which was maximal at 6 hr with complete recovery 24 hr after each dose beyond which no lymphocytopenia or T lymphocyte depletion was seen. Preservation of skin test positivity to recall antigens such as PPD and histoplasmin, rise in antibody titers to the secondary antigens tetanus and typhoid, and primary antibody response to KLH were found in both groups after treatment. Serum gamma globulin concentrations were unchanged. Five of six patients receiving 3 doses and three of six receiving 1 dose had satisfactory improvement in clinical parameters, with maximal benefit seen within the first 4 days. Six patients still felt better at 4 weeks, and one patient in each group entered a clinical remission greater than 16 weeks. We conclude that higher and repeated doses of MPS caused neither greater lymphocytopenia nor more prolonged suppression of recirculating lymphocytes than the conventional oral doses. The clinical benefits stem from reduction of inflammation, and it is doubtful that pulse therapy by itself induced significant generalized immunosuppression.