We examined the effect of a putative lipid peroxidation inhibitor, the 21-aminosteroid U74006F, on transient forebrain ischemia in rats. Acute-treatment rats received either 3 mg/kg U74006F (n = 7) or carrier vehicle (n = 5) intravenously 30 minutes before ischemia, sustained-treatment rats received the same treatment before ischemia followed by 3 mg/kg U74006F (n = 6) or carrier vehicle (n = 5) intraperitoneally every 6 hours for 48 hours, and control rats (n = 7) received no injection. Coronal magnetic resonance images were obtained daily for 3 days, followed by the histological examination of perfusion-fixed brains. Control rats demonstrated magnetic resonance image changes indicative of neuronal damage in the striatum at 24 hours postischemia, followed by changes in the hippocampus and neocortex at 48 hours. No significant effect of U74006F treatment on striatal or hippocampal injury was demonstrated. However, both the acute and sustained U74006F treatments produced a significant reduction in the severity of neuronal damage in the neocortex (p less than 0.05). Our results suggest that U74006F is of benefit in ameliorating ischemic neuronal injury, particularly in the neocortex, and raise the possibility of regional variability in lipid peroxidation following an ischemic insult.