Fentanyl is often used as an anesthetic supplement for short procedures because it has a rapid onset and brief duration of action. However, persistence of ventilatory depression several hours following the last dose has been seen. The authors studied the pharmacokinetics of fentanyl in the dog to find an explanation for the occasionally prolonged duration of action. 3H-fentanyl citrate, 10 or 100 μg/kg, was injected intravenously is dogs anesthetized with enflurane—O2. Arterial plasma and urine were analyzed for unchanged 3H-fentanyl and for total 3H radioactivity. Kinetic indices were derived by nonlinear least-squares analysis of log concentration (ng/ml) vs. time relationships. Initially, the elimination of fentanyl from plasma was very rapid, and 98 per cent of the amount administered was removed from plasma in the first 5 min after an intravenous injection. However, the terminal elimination phase was prolonged (t1/2 = 199 ± 17 min). The apparent volume of distribution was large (9.8 1/kg) and independent of dose. Repetitive doses produced an accumulation of fentanyl. 3H-labelled metabolites of fentanyl were present in the earliest samples of plasma, and accounted for the major portion of the total 3H radioactivity in both plasma and urine. Urine collected for six hours contained 36 per cent of the total 3H radioactivity administered, but only 4 per cent of fentanyl administered was excreted as unchanged fentanyl. The authors conclude that most of a single dose of fentanyl is rapidly eliminated from plasma (and presumably brain) by biotransformation to inactive metabolites and by uptake of the active drug by body tissues. The high affinity of tissues for fentanyl limits the rate of its ultimate elimination from the body by biotransformation and leads to accumulation of the drug when administered in very large or repeated doses. Under these circumstances the slow release of drug from tissues results in persistent plasma levels of fentanyl and a prolonged duration of action.