The disposition of antipyretic drugs is central to the understanding of their action in children. Accordingly, the authors measured plasma levels of acetaminophen and ibuprofen in 153 febrile children for 6 hours after a single dose of either acetaminophen (12.5 mg/kg) or ibuprofen (5 or 10 mg/kg). Cmax occurred about 2 1/2 hours before maximum antipyresis, when plasma acetaminophen or ibuprofen was 25 to 50% less than Cmax. Most plasma level data fit a one-compartment open model, and this suggests a pharmacodynamic basis for the observed lag between Cmax and maximum antipyretic response. Plasma levels (and AUC0[RIGHTWARDS ARROW]) of ibuprofen 10 mg/kg were less than expected for a two-fold increase in dose. For acetaminophen, the tlog was less than ibuprofen, Ka was more than ibuprofen, and β was less than ibuprofen. The ibuprofen β was not dose dependent, but the Vd was dose and model dependent. In contrast, ibuprofen Clp was dose and model independent. Acetaminophen pharmacokinetics were similar to those previously reported. Initial temperature, race, gender, prior medications, or diagnosis did not confound the results for ibuprofen or acetaminophen. Accordingly, a pharmacodynamic basis is a more likely explanation for the initial temperature effects found previously for antipyretic drugs in children. Ibuprofen (5 and 10 mg/kg) AUC0[RIGHTWARDS ARROW] was higher in the older (≥ 2.5 yrs) children and the Vd and Clp were lower in the older children, when discriminated by age or pharmacokinetic parameters. The observed dose dependency of AUC0[RIGHTWARDS ARROW] and the effect of age on ibuprofen disposition must be considered if pharmacokinetic interpretations are used to develop the antipyretic dose of ibuprofen in children.