The acute phase response is a cascade of events contributing to hypermetabolism and substrate catabolism. It was believed to persist for only a short time after injury. There is now evidence that systemic catabolism and hypermetabolism associated with thermal injury persevere for a long time. We hypothesize that the proinflammatory hepatic acute phase response perseveres for an extended time and enhances hypermetabolism longer than previously believed. Prospective study. Intensive Care Burn Unit, Shriners Hospital for Children. Twenty-three children (aged 1-16 years) sustaining a severe thermal injury (>/=40% total-body surface area) who remained in the intensive care unit longer than 30 days. Patient demographics, nutritional support, incidence of sepsis, inhalation injury, mortality, and levels of serum constitutive proteins, type I and type II acute phase proteins, free fatty acids, proinflammatory cytokines, insulin-like growth factor (IGF) I, IGF binding protein-1, IGF binding protein-3, and hepatocyte growth factor. After thermal injury, constitutive hepatic protein levels decreased 2- to 3-fold 80 days after burn, whereas acute phase protein levels increased. Free fatty acid levels were increased 5 days after burn. Proinflammatory cytokine levels (interleukin [IL] 1, IL-6, IL-8, IL-10, and tumor necrosis factor) and IGF binding protein-1 levels were elevated for 40 days after burn, whereas serum IGF-I and IGF binding protein-3 levels were decreased. Hepatocyte growth factor levels were increased immediately after burn but rapidly returned to the normal range. Despite adequate nutritional support, a severe thermal injury induces the proinflammatory acute phase response for a prolonged period. Thus, the liver with the hepatic acute phase response plays a more important role during catabolism after burn than previously believed. Pharmacologic agents that improve hepatic function may be an effective approach to attenuate hypermetabolism after trauma.