Plasma concentrations of thiopentone were determined at frequent intervals over the first 12 min following injection i.v. in 8 patients. Samples of arterial and peripheral venous blood were obtained in all subjects. In 6, central venous and in 2, internal jugular samples were also obtained. Thiopentone concentrations in arterial and central venous plasma did not differ significantly after 2 min. Differences between arterial and peripheral samples were significant for 2 min although, in some patients, considerable variability persisted for up to 9 min. In both patients from whom jugular venous samples were obtained, the difference between these and the peripheral plasma concentrations was marked. This difference may account for the appearance of acute tolerance. A computer model for this hypothesis is presented.