We studied morphine pharmacokinetics after a single intravenous dose of 0.1 mg/kg in 20 newborn infants, who were born at 26 to 40 weeks of gestation and were less than 5 days of age. In the 10 infants whose gestational age was less than or equal to 30 weeks, the mean (+/- SD) distribution half-life was 50 +/- 35 minutes, elimination half-life was 10 +/- 3.7 hours, and clearance was 3.39 +/- 3.28 ml/kg/min; the corresponding values for the three term infants were 19 +/- 8 minutes, 6.7 +/- 4.6 hours, and 15.5 +/- 10 ml/kg/min, respectively. The data suggested a trend of decreasing values for distribution and elimination half-lives with increasing gestation, but a considerable degree of variation was seen. The morphine clearance rate increased as a function of gestational age at a rate of 0.9 ml/kg/min per week of gestation. Between 18% and 22% of the drug was found to be protein bound. Four hours after the dose, the drug level remained greater than or equal to 12 ng/ml in 8 of 10 infants born at greater than or equal to 31 weeks of gestation. In 8 of 10 infants born at less than or equal to 30 weeks of gestation, similar levels were maintained at 8 hours after the initial dose. We conclude that (1) there is a marked degree of variation in morphine pharmacokinetics during the neonatal period, (2) nearly 80% of the intravenously infused drug remains free, which might explain the high sensitivity to morphine in this age group, and (3) during the first week of age, adequate blood levels can be maintained by administration of morphine at 4- to 6-hour intervals in term infants and at less frequent intervals in very premature infants (less than or equal to 30 weeks of gestation).