Histamine methyltransferase from pig antrum mucosa was inhibited by 33 H1-receptor antagonists, by the H2-receptor antagonists burimamide and metiamide and by the burimamide analogue 5-methylburimamide, which did neither act on H1-nor on H2-receptors. Whereas all H1-receptor blocking agents as well as metiamide and 5-methylburimamide inhibited the enzyme in a competitive manner, the type of inhibition found for burimamide was a mixture of non-competitive and uncompetitive with respect to histamine, which is similar to that one observed with 1-methylhistamine, the product of the histamine methylation reaction. Furthermore, all compounds tested — with the only exception of burimamide — activated the gastric histamine methyltransferase in lower concentrations, the most potent activator being piprinhydrinate (180% increase of the enzyme activity). This enhancement of 1-methylhistamine formation by antihistaminic drugs was not due to a true activation of the enzyme by increasingVmax, but was caused by partially abolishing the inhibition of histamine methyltransferase by so-called ‘optimum’ concentrations of histamine. Two explanations were given for the different mode of action of burimamide compared with that of metiamide and the other antihistaminic drugs: (1) The change in the type of inhibition from burimamide to metiamide seemed to be due to the introduction of a methylgroup into position 5 of the imidazole ring. (2) Burimamide and 1-, 2- and 3-methylhistamine were the only compounds tested in which the imidazole nucleus was substituted at position 4, but not at position 5, and which thus probably produced substrate or product inhibition.