Pentobarbital plasma levels were determined in 16 critical care patients receiving a dose of approximately 30 mg/kg/day and suffering from severe head injury. In 10 patients monitored more than six times, a continuous decrease in plasma concentrations, caused by a mean increase in pentobarbital total plasma clearance from 0.81 to 1.06 ml/min/kg, was found. This effect might be due to autoinduction of hepatic drug-metabolizing enzymes. As clearance values showed marked inter- and intraindividual variability, it is necessary to monitor pentobarbital plasma levels frequently to adapt the dosage to the changes in clearance. Infrequent determinations are of little clinical value, as the necessary changes in pentobarbital dosage will not be predicted precisely enough.