The present study evaluated the effect of the non-glucocorticoid 21-aminosteroid U74006F on the development of regional cerebral oedema after lateral fluid-percussion (FP) brain injury in the rat. Male Sprague-Dawley rats (n = 20) were anaesthetized and subjected to lateral FP brain injury of moderate severity (2.5-2.6 atmospheres). Fifteen minutes after brain injury, animals randomly received an i.v. bolus of either U74006F (3 mg/kg, n = 11) followed by a second bolus (3 mg/kg) at 3 hours vs buffered saline vehicle (equal volume, n = 9). At 48 hours postinjury, animals were sacrificed and brains tissue assayed for water content using wet weight/dry weight methodology. Administration of U74006F significantly attenuated the increase in water content observed in control animals in the ipsilateral hippocampus (adjacent to the site of maximal injury, p less than 0.05). Administration of U74006F also significantly reduced post-injury mortality from 28% in control animals to zero in treated animals (p less than 0.001). These results suggest that lipid peroxidation may be involved in the pathophysiological sequelae of brain injury and that 21-aminosteroids may be beneficial in the treatment of brain injury.