The pharmacokinetics of fentanyl were determined in human surgical patients using radioimmunoassay. Fentanyl was measured in the serum, cerebrospinal fluid (CSF), and urine of patients receiving 0.1, 0.5, or 1.0 mg/m2 of fentanyl intravenously. The kinetics of the disappearance of fentanyl from the serum were very similar at the three administered doses. At all doses, levels fell rapidly in the first five minutes to approximately 20% of the peak value. Thereafter, serum levels fell more slowly with an observed half-life (t 1/2) of approximately 10 to 20 min. depending on dose. By 2 hr serum levels had stabilized at low values (1, 5, and 8 ng/ml) and continued to decrease very slowly thereafter, with an observed t 1/2 of 1 to 2 hr at the low dose (0.1 mg/m2) and greater than 4 hr at 0.5 and 1.0 mg/m2. The serum elimination curves were dissected and described mathematically in terms of a three-compartment model. Urinary excretion of fentanyl accounted for 15% to 20% of the administered dose. Urinary excretion was very low during the first 2 hr, suggesting that this route of elimination is not important in terminating the actions of fentanyl in man. Fentanyl levels in the CSF of patients given terminating the actions of fentanyl in man. Fentanyl levels in the CSF of patients given the high dose (1 mg/m2) were low, and never exceeded 4 ng/ml. Peak levels of fentanyl in the CSF were not seen until at least 15 min after administration.