Plasma adrenocorticotrophin (ACTH), cortisol and aldosterone increased during and after iv administration of calcium gluconate in 4 normal subjects, one patient with hypoparathyroidism and one patient with hypothyroidism. On the other hand, there was a decrease in plasma renin activity but only in the normal subjects. Plasma ACTH and cortisol responses to calcium were abolished whereas plasma aldosterone response persisted in 2 normal subjects pre-treated with dexamethasone. The results observed after calcium administration were compared to those observed after infusion of the solvent only in 6 normal subjects and 4 thyroidectomized patients who were studied twice at 3 day intervals. Plasma ACTH, cortisol and aldosterone were higher when calcium was administered. Plasma renin activity was not statistically different whether or not calcium had been injected in the subjects studied twice. These results demonstrate a direct effect of calcium on ACTH and aldosterone secretion which is not mediated by calcitonin and parathyroid hormone. The stimulatory effect of calcium on cortisol secretion depends on the increase in plasma ACTH.