BACKGROUND An increasing body of evidence indicates that interferon (IFN )-gamma is an immunoregulator and may play a key role in the pathogenesis of autoimmune diseases, including rheumatoid arthritis (RA). OBJECTIVE To assess the efficacy and tolerability of anti-IFN-gamma in patients with active RA. METHODS In a randomized, double-blind trial, 30 patients with active RA were randomly assigned to receive intramuscular injections of anti-IFN-gamma, anti-TNF-alpha, or placebo for 5 consecutive days. RESULTS Both anti-cytokines were significantly superior to placebo. Patients stopping treatment due to lack of efficacy included I receiving anti-TNF-alpha, 2 receiving anti-IFN-gamma, and 9 receiving placebo. According to the physician's assessment, improvement was achieved by the 7th day in 9 patients receiving anti-TNF-alpha, 7 receiving anti-IFN-gamma, and 2 receiving placebo. By day 28 the corresponding figures were 8, 8, and 0, respectively. CONCLUSIONS Antibodies to IFN-gamma could be a promising approach to treating RA, especially its treatment-resistant forms.