Superoxide production by polymorphonuclear leukocytes (PMNs) and macrophages was inhibited by piroxicam and other non-steroidal anti-inflammatory drugs both in vitro and in vivo. Hitherto, data have only been available on blood PMNs and macrophages. In order to investigate the situation in the joint, PMNs were isolated from synovial fluid before and after 24 h of piroxicam treatment in patients with rheumatoid arthritis. Isolated PMNs were stimulated with PMA and serum-treated zymosan. The capacity of synovial fluid PMNs to produce superoxide decreased by 30% after piroxicam treatment. A similar decrease was found for blood PMNs. No difference in superoxide production was found between blood PMNs and synovial fluid PMNs which were obtained simultaneously. From the fact that the piroxicam concentration in synovial fluid was 40% of the serum value, it can be concluded that piroxicam probably became bound to PMNs before they entered the joint cavity. These results indicate that at the site of the inflammation the superoxide production by PMNs is inhibited by piroxicam treatment. The inhibition of superoxide production is probably important in the effect of piroxicam and other non-steroidal anti-inflammatory drugs in rheumatoid arthritis.