Reactive oxygen species (ROS) are important contributors to the secondary injury cascade following traumatic brain injury (TBI), and ROS inhibition has consistently been shown to be neuroprotective following experimental TBI. NXY-059, a nitrone free radical trapping compound, has been shown to be neuroprotective in models of ischemic stroke but has not been evaluated in experimental TBI. In the present study, a continuous 24-h intravenous infusion of NXY-059 or vehicle was initiated 30 min following a severe lateral fluid percussion brain injury (FPI) in adult rats (n=22), and histological and behavioral outcomes were evaluated. Sham-injured animals (n=22) receiving identical drug infusion were used as controls. Visuospatial learning was evaluated in the Morris water maze at post-injury days 11-14, followed by a probe trial (memory test) at day 18. The animals were sacrificed at day 18, and loss of hemispheric brain tissue was measured in microtubule-associated protein (MAP)-2 stained sections. Brain-injured, NXY-059-treated animals showed a significant reduction of visuospatial learning deficits when compared to the brain-injured, vehicle-treated control animals (p < 0.05). NXY-059-treated animals significantly reduced the loss of hemispheric tissue compared to brain-injured controls (43.0 +/- 11 mm3 versus 74.4 +/- 19 mm3, respectively; p < 0.01). The results show that post-injury treatment with NXY-059 significantly attenuated the loss of injured brain tissue and improved cognitive outcome, suggesting a major role for ROS in the pathophysiology of TBI.