Oral administration of repeated doses of activated charcoal to volunteers and dogs significantly increased the systemic clearance of intravenously administered theophylline and decreased its elimination half-life. This effect is most likely to be due to theophylline entering the gut and being adsorbed onto the charcoal. The mechanism by which intravenously administered theophylline enters the gut has been examined. Its biliary excretion after intravenous administration to patients with T-tube biliary drainage accounted for 0.28% of the dose and a similarly small biliary excretion was found in dogs. In the latter total biliary diversion had no effect on the clearance or half-life of theophylline after intravenous administration. In two dogs the theophylline content of jejunal aspirate was comparable with that of simultaneously withdrawn venous plasma samples. These results suggest that the presence of charcoal in the gut represents a sink adsorbing theophylline entering the lumen by diffusion across the intestinal wall, and by this mechanism it increases clearance of the drug even after intravenous administration.