The effects of in vitro carbamylation of plasma with potassium cyanate on the binding of sulfisoxazole and diazepam have been investigated. Incubation of plasma with potassium cyanate produced varying degrees of carbamylation of plasma proteins which were associated with a decrease in the binding of sulfisoxazole (100 mg/l), a drug bound to site I on the human albumin. Scatchard plots showed that this decreased binding resulted from a decrease in affinity without changes in the number of binding sites. Similar changes were detected in uremia. Carbamylation of plasma proteins did not affect the binding of diazepam (3 mg/l), a drug bound to site II. The plasma protein binding of sulfisoxazole and diazepam was decreased in samples from uremic patients. Charcoal treatment did not modify the binding of sulfisoxazole to normal or carbamylated plasma while it reduced, but did not normalize, the binding defect in uremic plasma. On the other hand, charcoal treatment brought the binding of diazepam in uremic plasma to normal values. It seems that only drug binding site I is carbamylated in uremia, while competitive displacers bind to sites I and II.