Previous studies at the NIH have demonstrated that in over 90% of cases of Wegener's granulomatosis (WG) and other systemic necrotizing vasculitides, glucocorticoid (GC) and daily low dose cyclophosphamide (CP) therapy has resulted in marked improvement and even remission. However, such therapy has been associated with about 50% relapses, 10% resistance to initial treatment and significant toxicity in almost all patients. Consequently, we have attempted to identify alternative therapies for the systemic vasculitides that would be less toxic then daily CP. An NIH study of the efficacy of intermittent high dose intravenous CP and daily GC (Protocol #88-I-56) revealed that 79% of 14 patients with WG either failed to respond to treatment, did not sustain improvement or could not tolerate continued treatment during a period of approximately two years. In another study (Protocol #89-I-18), we evaluated treatment with GC and weekly oral doses of methotrexate (MTX) in 15 patients with Takayasu's arteritis, in whom disease previously failed to be controlled with GC, GC + CP, or in whom remission with such treatment was followed by relapse. Fifty-three percent (8/15) of patients previously dependent on GC were able to achieve remission and discontinue GC therapy. Five of seven patients who remained on GC were in remission and receiving at least 50% less GC than prior to MTX therapy. Only three patients had progressive disease. The mean follow-up period was 20 months. We have also recently analyzed our results for MTX + GC therapy and 29 patients with WG. Seventy-six percent of patients had marked improvement and 69% achieved remission. Seventy-two percent of those in remission have not required GC therapy for a mean period 10 months. We conclude that weekly low dose MTX therapy is a feasible alternative to CP in the treatment of systemic vasculitis. Judgement of the ultimate value of such therapy should be deferred until a greater number of patients have been studied over a longer period of time.