The aetiology of rheumatoid arthritis is unknown but CD4+ T cells are known to be involved in its pathogenesis. Because of this, anti-CD4 monoclonal antibody has been used in open studies with clinical benefit in up to 60% of patients. We have used a chimaeric anti-CD4 monoclonal antibody (cM-T412, Centocor) in a randomized, double-blinded, placebo controlled trial as treatment for rheumatoid arthritis. Nine patients with active rheumatoid arthritis resistant to traditional disease-modifying drugs were recruited. Four received an intravenous 50 mg bolus of antibody, and three received 50 mg weekly for four consecutive weeks. Two patients received placebo. Despite a marked reduction (P less than 0.001) in peripheral blood CD4+ lymphocytes, there was no significant clinical improvement in any of these patients. The decrease in CD4+ lymphocyte number lasted one week after a single 50 mg dose of cM-T412 but was more prolonged in the patients who received four infusions. CD8+ T cells, CD16+ cytotoxic cells and CD14+ monocytes showed only a transient reduction. It may be concluded that the therapeutic efficacy of anti-CD4 therapy is not directly related to CD4+ T-cell lymphopenia.