The effect of histamine on sterol synthesis has been investigated in freshly isolated human mononuclear leukocytes from healthy subjects. Incubation of cells for 6 h in a medium containing lipid depleted serum led to a threefold increase in the incorporation of (14C)-acetate or tritiated water into sterols. Histamine 0.3 microM added to the incubation medium at zero time inhibited this induction by 35% with a sigmoidal log dose-effect curve. The receptors mediating this action were characterised pharmacologically by using selective H1- and H2-agonists and -antagonists. The H2-agonists impromidine and 4-methylhistamine mimicked the effect of histamine on sterol synthesis, the suppression being 42% and 31%, respectively, at a concentration of 1 microM. In contrast, the H1-agonist 2-pyridylethylamine did not affect the pathway. The H2-antagonist cimetidine (10 microM) but not the H1-antagonist mepyramine (10 microM) totally reversed the inhibition of sterol synthesis by histamine. The results provide evidence that sterol synthesis in human mononuclear leukocytes is regulated by histamine, which appears to act predominantly via H2-receptors.