The effects of three non-steroidal anti-inflammatory agents, indomethacin, carprofen, and piroxicam, on in-vitro IgM rheumatoid-factor (IgM-RF) production by peripheral-blood mononuclear cells were studied in lymphocytes isolated from the peripheral blood of rheumatoid-arthritis patients and of healthy young (age 20-40 years) and elderly (age 70-80 years) volunteers selected for their known in-vitro IgM-RF production. All three drugs in therapeutic concentrations inhibited IgM-RF production by approximately 50%. Addition of low doses of prostaglandin E2 (PGE2) (30 nmol/l) to the cultures containing indomethacin restored the IgM-RF production to the original levels. Neither indomethacin nor PGE2 had any effect on IgM-RF production if the T cells were irradiated before culture. Endogenous PGE2 seems to stimulate IgM-RF production through an effect on a radiosensitive T-cell population. Non-steroidal anti-inflammatory agents block PGE2 production and therefore reduce IgM-RF production in vitro. These results suggest a new mechanism for the beneficial effect of prostaglandin synthetase inhibitors in the treatment of rheumatoid arthritis. © 1982.