1. Thiol methyltransferase (TMT) is a microsomal enzyme catalyzing the S-methylation of aliphatic sulphydryl drugs and xenobiotics. Studies of the functional significance of S-methylation catalysed by TMT have been hampered by lack of a potent, relatively specific, non-toxic inhibitor of the enzyme. 2. Human hepatic microsomal TMT was inhibited by the arylalkylamine 2,3-dichloro-alpha-methylbenzylamine (DCMB), and by a series of arylalkylamines, as well as the arylamine, aniline. 3. Inhibition kinetic studies with DCMB, benzylamine, aniline, phenylethylamine and phenylethanolamine, five compounds with a wide range of IC50 values, showed 'mixed' inhibition of TMT with respect to the methyl acceptor substrate, 2-mercaptoethanol. Kis and Kii values were, respectively, 1.1 and 0.29 microM for DCMB, 160 microM each for benzylamine, 680 and 370 microM for aniline, 1640 and 1380 microM for phenylethylamine, and 2300 and 1400 microM for phenylethanolamine. Inhibition was at least partially reversible. 4. H.p.l.c. analyses were carried out with the products of enzyme reactions performed in the presence of aniline, benzylamine, and phenylethylamine to ascertain whether these compounds inhibited TMT by acting as methyl acceptors. Results showed that they did not act as methyl acceptor substrates.