Drugs that interfere with the immune responsein vitro, such as azathioprine (AZ), have been used extensively since 1964 in clinical therapeutic trials of autoimmune diseases. However, few adequately controlled studies are available concerning the concurrent effect of AZ on the immune and clinical responses to treatment of rheumatoid arthritis (RA). Thirty patients suffering from classical seropositive RA received AZ (1.5 – 2.0 mg/kg/day) and placebo in a controlled clinical cross-over study for two 12-week periods. Other treatments were kept constant throughout the entire 6 months. In terms of the clinical responses of joint count and grip strength patients receiving AZ improved markedly, in contrast to the placebo group. After 2 months, joint scanning revealed no progress of the disease in patients undergoing AZ treatment. Corresponding with the remarkably beneficial clinical effect of AZ, a significant drop in immunoglobulins was observed. However, since AZ failed to suppressin vivo specific antibody synthesis in RA, the question remains as to whether this drug actually does interfere with the autoimmunogenesis of the disease.