Background Analgesic acetaminophen (INN, paracetamol) plasma concentrations after major surgery in neonates and infants have not yet been established in the literature. We therefore conducted a study in our intensive care unit. Methods Forty children, mean (standard deviation) age, 10.3 (2.3) months, received 20 mg/kg acetaminophen either orally (n = 20) or rectally (n = 20) every 6 hours after a rectal loading dose (40 mg/kg) during elective craniofacial correction. Blood samples were taken 1 hour before and 2 hours after administration of acetaminophen maintenance doses; pain scores were obtained every 3 hours. Results Acetaminophen plasma concentrations were higher in patients receiving rectal acetaminophen (mean area under the concentration‐time curve [AUC], 171.2 mg · h/L) than in patients receiving oral acetaminophen (mean AUC, 111.9 mg · h/L). Pain scores were higher in patients receiving oral acetaminophen. However, after exclusion of the patients who vomited from the group receiving oral acetaminophen, acetaminophen plasma concentrations and pain scores did not differ between the groups. There was no relation between acetaminophen plasma concentrations and pain scores. Although 9 of all 40 patients (22.5%) did not reach the expected analgesic acetaminophen plasma concentrations of 10‐ to 20 mg/L, Clinical Pharmacology & Therapeutics (2001) 70, 82–90; doi: 10.1067/mcp.2001.116794