30 patients with active classical rheumatoid arthritis affecting the knee took part in a 12-week double-blind trial in which intra-articular injections of orgotein (4 mg/week for 6 weeks) were compared with intra-articular aspirin 4 mg/week for 6 weeks. After 12 weeks clinical and biochemical assessments showed that orgotein was superior to aspirin. Clinical response was measured in terms of the cumulative rheumatoid activity index (RAI) which was based on scores for morning stiffness, range of flexion, pain and 25-foot (7.5 m) walking time. Treatment with orgotein resulted in significant improvement of the RAI; the improvement correlated with findings on knee-joint scanning which showed reduced mean uptake of 99mTc-pyrophosphate. After intra-articular orgotein injections, synovial fluid IgM and IgG rheumatoid factor levels fell significantly; so did prostaglandin E2 formation and lactate dehydrogenase activity. The changes in the synovial fluid suggest that the anti-inflammatory properties of orgotein may lie in its effect on proliferating synovia.