The effect of anti-inflammatory drugs on prostaglandin production by rheumatoid synovial tissue has been investigated. Synovial explants were maintained in tissue culture for periods up to six days and PGE2 concentrations in culture were determined by radioimmunoassay. The more potent nonsteroidal inhibitors of PGE2 production and their IC50 (micrometer) values were indomethacin 0.005, flufenamic acid 0.2, flurbiprofen 0.6, ibuprofen 2.0 , naproxen 6.0, phenylbutazone 10.0, and aspirin 20.0. Drugs with weak or insignificant effects were hydroxychloroquin, acetaminophen, azathioprine, chloroquin, penicillamine, gold Na thiomalate, and Na salicylate. Glucocorticoids were potent inhibitors; dexamethasone 0.003, prednisolone 0.01, hydrocortisone 0.03; while mineralocorticoids deoxycorticosterone and aldosterone were inactive at 1.0 micrometer. There is a reasonably good correlation between the IC50 concentrations of the nonsteroidal inhibitors and their peak free plasma concentration achieved during therapy in man. Inhibition of prostaglandin synthesis may contribute to the effects of many but not all anti-inflammatory drugs.