Cimetidine (400 mg b.d.), ranitidine (150 mg b.d.) and placebo were administered for 1 week to 6 healthy male volunteers in a randomized double-blind cross-over fashion. Hormonal concentrations before and after a TRH test were assessed before and after each treatment. A spontaneous decrease in the hormonal response to TRH was observed after placebo treatment. Both cimetidine and ranitidine induced a significant increase in basal prolactin (PRL) values. Neither TSH nor T3 were modified by cimetidine or by ranitidine. The basal concentration of reverse T3 was increased during cimetidine treatment. There was a significant rise in post-TRH T4 after cimetidine and ranitidine administration. These results suggest a role for histamine H2 receptors in the secretion of PRL and T4. Moreover, cimetidine affects the hepatic metabolism of thyroid hormones.