The protein binding of tolfenamic acid in plasma from patients with renal and hepatic disorders was studied by equilibrium dialysis. Drug binding to the cellular components of whole blood and blood cell suspensions was also measured. Salicylic acid was used as the reference drug in all experiments. Renal and hepatic diseases increased the unbound fraction of tolfenamic acid. Free drug fractions were significantly correlated with changes in creatinine, urea, and total bilirubin, but not with those in albumin or total protein in plasma. Comparison of the theoretical binding parameters in control plasma and similar changes in protein binding in all the plasma samples studied revealed that tolfenamic acid and salicylic acid probably share a common primary binding site. The significance of the correlation permits use of salicylic acid as a model drug for predicting changes in the protein binding of tolfenamic acid. The measurements of binding properties in whole blood and blood cell--buffer suspension showed that tolfenamic acid interacts with the lipid membrane structures of blood cells, while salicylic acid is distributed into the aqueous cell space.