We examined the effect of treatment with piroxicam, a nonsteroidal antiinflammatory drug (NSAID), on immunoglobulin (Ig) and IgM-rheumatoid factor (IgM-RF) synthesis in vitro by lymphocytes of patients with rheumatoid arthritis (RA). Oral treatment with piroxicam induced a progressive decrease of spontaneous IgM-RF production by unstimulated lymphocyte cultures during 12 weeks of observation. Also, pokeweed mitogen (PWM)-driven Ig synthesis was significantly diminished and the effect on total IgM production was sustained until the end of the study. This modulation of humoral responses is consistent with the drop in RF sera level. In addition, we also showed that treatment with NSAIDs can decrease RF levels in the synovial space. NSAIDs may have a long-term beneficial effect in patients with RA due to their modulatory role of lymphocyte responses. © 1988 Springer-Verlag.