Cimetidine, an H2 receptor antagonist, was given for 6 weeks to six normal male volunteers to study the effects on pituitary, adrenal, thyroid, and testicular hormone secretion. Patients were studied before (day 1) and after (day 42) cimetidine (300 mg four times daily) therapy, and four of the six were restudied after discontinuing cimetidine for 1 month (day 72). Basal TSH concentrations and responses to TRH administration as well as T3 RIA and T4 resin uptakes did not change during or after cimetidine therapy. The diurnal rhythm of plasma cortisol and maximum cortisol response to insulin (0.15 u/kg) were similar on days 1 and 42, but urinary free cortisol excretion fell 31% (Pless than 0.01). Response of GH to exercise, 100 g carbohydrate ingestion and insulin were unchanged, but mean nocturnal GH secretion decreased 33% (P less than 0.025) on cimetidine, and returned to baseline on day 72. The 24-h plasma prolactin profile was unchanged as was the prolactin response to insulin and TRH stimulation. Plasma FSH was not altered, but mean LH concentrations decreased 20% on cimetidine and continued to decline (45% of day 1 levels) after discontinuation of cimetidine (P less than 0.01). Spontaneous LH pulse amplitude declined slightly on day 42, but became significantly lower on day 72 (P less than 0.05). Peak LH responses t gonadotropin-releasing hormone were also reduced on cimetidine therapy (P less than 0.02). Plasma testosterone concentrations did not change but plasma oestradiol concentrations were 38% lower (P less than 0.025) after cimetidine was discontinued. H2 histamine receptors are involved in the control of multiple hormone secretory patterns and blockade of these receptors by cimetidine alters hormone profiles. These changed patterns have to be considered in the interpretation of hormone measurements in patients receiving cimetidine therapy.