Nimesulide is a preferential cyclo-oxygenase-2 inhibitory non-steroidal anti-inflammatory drug has, infrequently, been associated with hepatic reactions. To establish the extent of formation of various metabolites (some of which might be hepato-reactive) the whole body metabolism, plasma kinetics and routes of excretion of the radio-labelled drug was undertaken in 4 fasted male volunteers following an oral dose of 100 mg [ 14 C]-nimesulide. Urine, faecal and plasma samples were collected up to 168 h post dose, the total radioactivity and plasma concentrations of nimesulide and its principle metabolite, 4-hydroxynimesulide, were determined. Radio labelled metabolites in these samples was identified by combined liquid chromatography-mass spectrometry. The mean elimination half-life of total radioactivity in the plasma and whole blood was circa 4.8 h; the ratio whole blood and plasma being circa 0.6 h. The mean elimination half-lives for nimesulide and 4-hydroxynimesulide in plasma were circa 2.5 h and circa 3.9 h, respectively. The drug was rapidly excreted and recoveries were 59-66% in the urine and 33-39% in the faeces at 168 hours. A total of 16 metabolites were identified including the conjugated metabolites, which exceeds the 5 previously identified. Nimesulide was to be metabolised by 5 pathways involving (a) cleavage of the molecule at the ether linkage (b) reduction of the NO 2 group to NH 2 , and (c) ring hydroxylation followed by conjugation with either glucuronic acid or sulphate. In conclusion, the biotransformation pathway for nimesulide in man has now been comprehensively determined with 92% of the urinary metabolites fully characterised. The identification of some rare metabolites of nimesulide may help in understanding the mechanisms of hepatotoxicity from this drug.