Formation of the oxygen radical superoxide anion is one of the final events of several metabolic pathways in the cascade that leads to delayed neuronal death after traumatic or ischemic brain injury. In the laboratory, scavenging of the superoxide anion with native superoxide dismutase (SOD) or polyethylene glycol (PEG)-conjugated SOD (PEG-SOD) has been shown to be beneficial in several types of traumatic and ischemic injury. Accordingly, PEG-SOD was utilized in a randomized controlled Phase II trial to evaluate its safety and efficacy in severely head-injured patients with a Glasgow Coma Scale score of 8 or less. At two institutions, 104 patients were randomly assigned to receive either placebo or PEG-SOD (2000, 5000, or 10,000 U/kg) intravenously as a bolus, an average of 4 hours after injury. Prognostic factors were evenly distributed in the four groups, except for mean age which was significantly higher in the group receiving 10,000 U/kg than in the placebo group (mean age 34 years vs. 25 years). No complications attributed to the study medication were noted. The average intracranial pressure (ICP) was similar in the four groups, but the percentage of time during which ICP was above 20 mm Hg was less in the groups receiving 5000 or 10,000 U/kg of PEG-SOD. Patients in the group receiving 10,000 U/kg also required less mannitol for ICP control than the placebo group. Outcome was assessed using the Glasgow Outcome Scale at 3 and 6 months postinjury in 91 and 93 patients, respectively, by blinded observers not involved in the clinical management of the patients. At 3 months, 44% of patients in the placebo group were vegetative or had died, while only 20% of patients in the group receiving 10,000 U/kg of PEG-SOD were in these outcome categories (p < 0.03, multiple logistic regression test); at 6 months, these figures were 36% and 21%, respectively (p = 0.04). Differences in outcome between the placebo group and either of the other two dosage groups were not statistically significant. It is concluded that PEG-SOD was generally well tolerated and appears promising in improving outcome after severe head injury. A larger, multicenter, Phase III trial, using a higher dose (20,000 U/kg) compared to placebo and to 10,000 U/kg of PEG-SOD is planned.