Plasma levels of fentanyl were analyzed in 12 infants undergoing extracorporeal membrane oxygenation who received a fentanyl bolus (5 to 10 micrograms/kg) followed by infusion at 1 to 6.3 micrograms/kg/hr. Fentanyl levels, averaging 11 samples/infant, were measured by radioimmunoassay (mean 19.7 +/- 35.7 ng/ml; n = 140). Eight of the infants, all with a primary diagnosis other than congenital diaphragmatic hernia, survived with relatively short (< 7 days) courses on extracorporeal membrane oxygenation; this group of infants did not develop tolerance to fentanyl and could be maintained on infusion rates of < 5 micrograms/kg/hr throughout. The four infants with congenital diaphragmatic hernia had longer extracorporeal membrane oxygenation runs and three did not survive; their plasma fentanyl levels were consistently higher and while the infusion rates were higher early on extracorporeal membrane oxygenation, they did not exceed 7 micrograms/kg/hr and actually decreased after 5 days on extracorporeal membrane oxygenation. Five infants (42%) received lorazepam in addition to fentanyl for at least one sampling time. The fentanyl infusion dose and plasma level were higher in the congenital diaphragmatic hernia nonsurvivors who did not receive lorazepam (p < 0.001). A decrease in fentanyl clearance correlated with renal dysfunction (p < 0.01). A bolus of fentanyl followed by infusion of relatively low doses (1 to 5 micrograms/kg/hr) provides adequate analgesia for infants on extracorporeal membrane oxygenation, particularly when it is supplemented with intravenous lorazepam whenever needed to control infant movement.