A prospective study was performed of antiepileptic drug levels in 14 boys resident in a pediatric chronic care facility. Blood samples and 24-hour urine collections were obtained monthly. During febrile illness (temperature > 101 °F for more than 24 hours), six additional blood samples and two urine collections were obtained for each child. During 8 of 10 febrile illnesses, phenytoin (PHT) decreased more than 40% from pre-illness baseline. Mean PHT level before illness was 16.7 (± 4.5 μg/ml) and during illness, 8.2 (2 3.6 μg/ml), significantly lower (p < 0.001). Neither PHT binding nor absorption was altered by illness, so the most probable cause of the drop in PHT levels was induction of the hepatic oxidative enzyme system.