Pentagastrin stimulates the release of calcitonin from normal C-cells in the human thyroid. In the present investigation the effect of cimetidine on the liberation of calcitonin in response to intraarterial pentagastrin (0.6 μg · kg −1) was studied in 14 normocalcaemic patients undergoing surgery for thyroid adenomas. Cimetidine was administered as a bolus injection of 200 mg followed by an intravenous infusion of 1.5 mg · kg −1 · h −1. In seven patients not given cimetidine, mean calcitonin concentration in the thyroid vein rose from 419 ± 58 to 2787 ± 645 pM in response to pentagastrin. In seven patients given cimetidine, mean calcitonin concentration only increased from 107 ± 33 to 166 ± 51 pM after pentagastrin. The difference between the two groups was statistically significant both during basal conditions ( P < 0.001) and in response to pentagastrin ( P < 0.01). The results suggest that pentagastrin affects normal C-cells via release of histamine and that cimetidine markedly interferes with this mechanism.