A variety of histamine agonists, antagonists and their analogs were tested for their ability to inhibit histamine-N-methyltransferase. Our initial studies showed that the enzyme is inhibited noncompetitively by the histamine H2 receptor agonists, Dimaprit, and we suggested that the enzyme possessed an inhibitory site with an affinity for both Dimaprit and histamine. The most potent inhibitors possessed in addition to a side chain ammonium group a thiourea or imidazole group which, like the imidazole group of histamine, is capable of prototropic tautomerism. The H1 receptor agonists, 2-pyridyl-beta-ethylamine and 2-thiazolyl-beta-ethylamine, which do not undergo prototropic tautomerism, were only weakly inhibitory. There was no correlation, however, between pharmacological and inhibitory activity. The most potent inhibitor (K1 approximately 10 to the minus 6th power M) was a Dimaprit analog, SKF Compound 91488, which has no histamine agonist activity. Compound 91488 may, therefore, be especially useful in studies of histamine metabolism.