During levamisole therapy, 14 of 20 patients with previously unresponsive rheumatoid arthritis had significant improvement (P < 0.05) in clinical measures of disease activity, erythrocyte sedimentation rate, and rheumatoid factor titer in a 32-week double-blind placebo controlled crossover trial. Levamisole was shown to alter antibody responses to tetanus and typhoid antigens, lymphocyte blastogenesis to phytohemagglutinins, and the number of null cells in peripheral blood. Agranulocytosis and rash resulted in discontinuation of the drug in one patient in each group. Though clearly effective, routine use of levamisole as a disease suppressant in rheumatoid arthritis must await more complete clarification of its association with agranulocytosis.Recent reports suggest that dysfunction of the cellular limb of the immune system may be of significance in the pathogenesis of rheumatoid arthritis (1-13).Levamisole is an agent capable of potentiating the activity of a suppressed immune system with preferential effects on the cellular limb (14-19). It has been reported to be of benefit in the treatment of patients Address reprint requests to Harold E. Paulus, MD, 1000 Veteran Avenue, Los Angeles, California 90024.Submitted for publication June 28, 1979; accepted in revised form October 22, 1979. whose rheumatoid arthritis has been refractory to conventional modes of therapy. Twenty patients with rheumatoid arthritis were studied to evaluate the effects of levamisole on clinical and laboratory parameters of efficacy and on immunologic variables and their correlation with clinical effect. The frequency and types of adverse reactions were also evaluated.The study was designed not only to assess the overall efficacy of levamisole, but also to evaluate the utility of the crossover design. The spectrum of effects of levamisole versus placebo was assessed in a parallel fashion during the initial 16 weeks of the study. Crossover from levamisole to placebo permitted careful evaluation under controlled double-blind conditions of the duration of effects of levamisole after its discontinuation.