Thiopental kinetics and protein binding were determined in 7 surgical patients with chronic renal failure and a thiopental-free fraction of 28.0 .+-. 6.5% and in 7 age- and weight-matched normal surgical patients with a thiopental-free fraction of 15.7 .+-. 2.4%. Thiopental clearance, based upon total plasma concentrations, rose from 3.2 .+-. 0.6 ml/kg per min in the normal group to 4.5 .+-. 1.1 ml/kg per min in the chronic renal failure group. Volume of distribution at steady state, also based on total drug concentrations, rose from 1.9 .+-. 0.5 l/kg in the normal group to 3.0 .+-. 1.0 l/kg in the chronic renal failure group. These changes in clearance and volume of distribution at steady state are secondary to changes in free drug distribution and elimination. When kinetics were calculated from free drug concentrations, the intrinsic clearance, unbound volume of distribution at steady state, and free fraction in tissues in the normal and renal failure groups did not differ substantially. Evidently, the kinetic changes based on total drug concentrations are secondary to changes in free fraction in plasma. In chronic renal failure patients, the underlying rate and extent of thiopental distribution and elimination are much the same as in normal patients.