Despite its wide use, the mechanism of action of paracetamol (acetaminophen) is uncertain. It is commonly stated to be a weak inhibitor of the synthesis of prostaglandins (PGs) by the prostaglandin H synthases (COX-1 and COX-2) but paracetamol inhibits the synthesis of PGs in stimulated cultured cells with IC₅₀ values ranging from 4 to 200 _M. Paradoxically, it generally stimulates PG production in broken cell preparations. Here we show that paracetamol inhibits the production of PGs in human rheumatoid synoviocytes during stimulation by interleukin1 (0.1ng/ml) for 18 h. Paracetamol inhibited the production of both PGE₂ and PGF₂with median IC₅₀ values of 7.2 and 4.2 _M respectively, without affecting the or the level of the constitutive enzyme, COX-1 or the interleukin-1 mediated induction of both COX-2 and cytosolic phospholipase A₂- (cPLA₂-). These data indicate that paracetamol suppresses delayed PG production by direct modulation of the cPLA₂- /COX-2 pathway at therapeutic concentrations. Paracetamol is a substituted phenol and its effects on the synthesis of PGs are very similar to those of other phenols. Paracetamol should be considered to inhibit the production of PGs although the cause of its selectivity; analgesic and antipyretic effects with weak antiplatelet and anti-inflammatory effects is unknown.