To evaluate the mechanism of cyclosporine-induced hyperkalemia, the renin-angiotensin-aldosterone system and renal potassium clearance were compared in ten renal transplant recipients treated with cyclosporine and treated with azathioprine. After stimulation by a low-sodium diet and furosemide, cyclosporine-treated patients demonstrated lower plasma renin activity when supine (1.9 ± 0.3 v 7.8 ± 1.4 ng/mL/hr) and after standing (3.0 ± 0.7 v 12.2 ± 1.5 ng/mL/hr). Supine plasma aldosterone levels tended to be lower in cyclosporine-treated patients. (4.8 ± 0.8 v 10.5 ± 2.6 ng/dL), although standing plasma aldosterone levels were not different (10.8 ± 3.0 v 12.3 ± 2.0 ng/dL). After administration of 0.75 mEq of potassium chloride per kilogram of body weight, cyclosporine-treated patients excreted 52% ± 7.1% of the potassium load in six hours compared with excretion of 67% ± 7.0% by the azathioprine-treated patients, although there was no difference in plasma aldosterone levels in response to the potassium load in the two groups. These data suggest that cyclosporine causes suppression of plasma renin activity and a tubular insensitivity to aldosterone, both of which may impair potassium excretion.