In order to investigate the effect of chronic hypercortisolaemia on endogenous natriuretic factors (atrial natriuretic hormone (ANH) and the Na+/K+ pump inhibitor) digitalis-like substance (DLS), and their relation to hypertension, 28 patients with pituitary- or adrenal-dependent Cushing's syndrome and six patients on high-dose prednisone treatment were studied. Plasma ANH levels were increased in patients with Cushing's syndrome (36.0 +/- 1.4 (S.E.M.) ng/l) compared with those in healthy controls (28.6 +/- 1.3 ng/l, P less than 0.01). In prednisone-treated patients, ANH levels (43.8 +/- 4.5 ng/l) were higher than those in patients with Cushing's syndrome and in controls (P less than 0.05 and P less than 0.01 respectively). DLS measured by radioimmunoassay and binding of [3H]ouabain to erythrocytes was not altered in patients with hypercortisolaemia. Slightly decreased DLS activity in the erythrocyte 86Rb uptake inhibition assay was found in patients with Cushing's syndrome (52.9 +/- 2.7%) compared with that in controls (60.9 +/- 1.8%, P less than 0.02). With the exception of cortisol (r = 0.52, P less than 0.01), none of the other factors determined correlated with the mean arterial pressure in patients with Cushing's syndrome. Thus, a chronic excess of endogenous and exogenous glucocorticoids increases plasma levels of ANH, but does not substantially influence DLS activity or plasma levels. Neither natriuretic factor is directly related to hypertension in Cushing's syndrome.