Responses to histamine were potentiated by 17β-estradiol in untreated and reserpine-treated aortic strips. 17β-Estradiol produced significantly greater potentiation after inhibition of diamine oxidase with iproniazid. Amodiaquine and quinidine, two known inhibitors of imidazole-N-methyltransferase, enhanced responses to histamine and abolished the potentiating effect of 17β-estradiol. Also, contractions produced by histamine were not increased by amodiaquine or quinidine in the presence of 17β-estradiol. Responses to histamine were increased only slightly by testosterone and hydrocortisone, and these effects were also blocked by known inhibitors of N-methylation. Responses to 1,4-methylhistamine, the N-methylated metabolite of histamine, were not enhanced by 17β-estradiol or amodiaquine, and in only one of six strips by quinidine. Studies with the oil immersion technique indicated that imidazole-N-methyltransferase is a major mechanism terminating the action of histamine in aortic strips. The rate of N-methylation was significantly decreased by amodiaquine, quinidine, and 17β-estradiol. It is concluded that the steroid hormones enhance responses of vascular tissue to histamine by inhibiting N-methylation. Contractions of rabbit ileum by histamine were not increased by 17β-estradiol, perhaps owing to a dominant depressant effect of the steroid on the amplitude of spontaneous contractions.