We measured cortisol binding to albumin in uremic plasma during a study to see if increased morning plasma free cortisol values, reported previously in chronic renal failure patients, could be explained by binding abnormalities of plasma proteins. Cortisol binding was measured in plasma from chronic renal failure patients and compared to values in normal controls. The unbound and albumin-bound fractions of plasma cortisol were determined using an isocolloidosmolar equilibrium dialysis method and heat inactivation of corticosteroid-binding globulin. A lower ratio of albumin-bound cortisol to unbound cortisol was seen in uremic than in nonuremic plasma (p less than 0.05). This difference was eliminated when uremic plasma was treated with dextran-activated charcoal. These studies suggest that cortisol binding to albumin is decreased in uremic plasma because of a heat-stable substance which is removed from plasma by charcoal treatment.