The acute response to injury and infection is manifested by increased synthesis of acute-phase proteins by the liver, an increased white blood cell count, fever, a negative nitrogen balance, and altered serum mineral levels (zinc, iron, and copper). This response is thought to be partially mediated by cytokines such as interleukin-1, but has not been well studied in head-injured patients. In this study, 25 patients were studied for evidence of the acute-phase response extending from hospital admission up to 21 days postinjury. The patients were divided into two groups to determine if severity of injury influenced the response. Group 1 consisted of nine patients with admission peak 24-hour Glasgow Coma Scale (GCS) scores of 4 or less; Group 2 consisted of 16 patients with admission peak 24-hour GCS scores of 8 or greater. All patients demonstrated some evidence of the acute-phase response. Serum alpha-1 acid glycoprotein, ceruloplasmin, and C-reactive protein levels were elevated on admission and throughout the study. Serum albumin and zinc levels were depressed on admission; zinc levels gradually normalized by Day 21 in both groups, but hypoalbuminemia was observed throughout the study period. Serum copper levels were normal on admission but increased to above normal in both groups by Day 11 postinjury. Urinary urea nitrogen excretion was elevated in both groups and peaked on Day 7 for Group 1 and Day 11 for Group 2 patients. The patients with admission GCS scores equal to or less than 4 had overall higher temperatures than were seen in those with GCS scores greater than or equal to 8 (p = 0.009). All patients but one had an elevated white blood cell count on admission. It is concluded that brain-injured patients with admission GCS scores of 3 to 4 and 8 to 14 demonstrate an acute-phase response which lasts for at least 3 weeks postinjury. It is speculated that this response is at least partially mediated by increased intraventricular interleukin-1 activity.