SUMMARY: The uptake of cortisol by the gastro-intestinal tract and by the liver was estimated in sheep by measurement of [3H]cortisol concentrations in portal and hepatic venous plasma during constant infusion of tritium-labelled cortisol, with simultaneous measurement of plasma flows. The total splanchnic uptake of cortisol was 57 ± 4 (s.e.m.)% of the measured rate of cortisol secretion, 45% by the liver and the remainder by the gastro-intestinal tract. The splanchnic extraction of cortisol could be related to plasma flow, and was less efficient at higher flows. It could also be related to plasma cortisol concentration, and was more efficient at higher concentrations. The splanchnic uptake of cortisol was closely correlated with the flow of unbound cortisol into the region, and was 1·61 times that influx. There is therefore partial dissociation of plasma protein-bound cortisol during the splanchnic uptake. About 25% of secreted cortisol is converted to cortisone at extrahepatic sites, and is removed from plasma by the liver.