Objectives: To determine the antipyretic efficacy of acetaminophen (IV, enteral, rectal) and ibuprofen (enteral) in critically ill febrile pediatric patients. Design: Retrospective cohort study. Setting: Quaternary care pediatric hospital ICUs. Patients: Pediatric patients less than 19 years old who were febrile (>= 38.0 degrees C), received a dose of IV acetaminophen, enteral acetaminophen, rectal acetaminophen, or enteral ibuprofen and had at least one temperature measurement in the following 6 hours. Interventions: None. Measurements and Main Results: A total of 3,341 patients (55.8% male, median age 2.5 yr [interquartile range, 0.63-9.2 yr]) met study criteria. Baseline temperature was median 38.6 degrees C (interquartile range, 38.3-38.9 degrees C) measured via axillary (76.9%) route. Patients became afebrile (87.5%) at median 1.4 hours (interquartile range, 0.77-2.3 hr) after the first dose of medication, a -2.9 +/- 1.6% change in temperature. Antipyretic medications included as follows: enteral acetaminophen (n = 1,664), IV acetaminophen (n = 682), rectal acetaminophen (n = 637), and enteral ibuprofen (n = 358). Enteral ibuprofen had a significantly greater odds of defervescence on multivariable logistic regression analysis (p = 0.04) with a decrease of -1.97 +/- 0.89 degrees C while IV acetaminophen was significant for a decreased time to defervescence at median 1.5 hours (interquartile range 0.8-2.3 hr) after a dose (p = 0.03). Patient age, presence of obesity, and baseline temperature were significant for decreased antipyretic efficacy (p < 0.05). Conclusions: Enteral ibuprofen was the most efficacious antipyretic and IV acetaminophen had the shortest time to defervescence.