Cortisol 11β-hydroxysteroid dehydrogenase (11β-HSD) deficiency was observed in four patients with apparent mineralocorticoid excess. The 11β-HSD deficiency was demonstrated by a markedly decreased urinary tetrahydrocortisone/tetrahydrocortisol (THE/THF) ratio (>1 in normal children) during infusion of ACTH and administration of hydrocortisone. We propose that in these patients the 11β-HSD deficiency impairs the metabolism of cortisol to cortisone, resulting in a prolonged cortisol half-life, suppression of ACTH, and normal serum cortisol. The 11β-HSD deficiency protects the patient from adrenal insufficiency despite the low cortisol secretion; the prolonged half-life of cortisol may contribute to the hypertension and hyporeninemia observed in this disorder. Continuous intravenous hydrocortisone administration resulted in increased blood pressure and decreased serum potassium. Addition of spironolactone during continued administration of 20 mg per day of hydrocortisone resulted in a decrease in blood pressure and a rise in serum potassium. These studies suggest that an abnormality in cortisol action or metabolism results in cortisol behaving as a potent mineralocorticoid. These findings may account for this syndrome of apparent mineralocorticoid excess.