PURPOSE To evaluate the therapeutic efficacy of two antiepileptic compounds, RWJ-333369 and RWJ-333369-A in a well-established experimental model of lateral fluid percussion (FP) traumatic brain injury (TBI) in the rat. METHODS Anethestized Male Sprague-Dawley rats (n=227) were subjected to lateral FP brain injury or sham-injury. Animals were randomized to receive treatment with RWJ-333369 (60 mg/kg, p.o.) or its analog RWJ-333369-A (60 mg/kg, p.o.), or vehicle (equal volume) at 15 minutes, 4, 8, and 24 hours post-injury. In Study I, animals were assessed at 48 hours for acute motor and cognitive function and then sacrificed to evaluate regional cerebral edema. In Study II, animals were evaluated post-injury for motor function at 48 hours and weekly thereafter from 1 to 4 weeks. Post-traumatic learning ability was assessed 4 weeks post-injury, followed by evaluation of hemispheric tissue loss. RESULTS In Study I, no improvement in acute memory or motor function was observed following administration of either RWJ-333369 or RWJ-333369-A in brain-injured animals compared to vehicle-treated, brain-injured animals. However, brain-injured animals receiving treatment with RWJ-333369-A had a significant reduction in post-traumatic cerebral edema in both injured and contralateral hippocampus compared to brain-injured, vehicle-treated controls (p<0.05). In Study II, treatment with either compound did not result in any improvement of neuromotor function, learning ability or change in lesion volume following brain injury. CONCLUSION These results indicate that the novel antiepileptic compound RWJ-333369-A reduces post-traumatic hippocampal edema without affecting neurobehavioral or histological outcome. It remains unclear whether this small effect on hippocampal edema ie related to the ability of this compound to attenuate seizure activity.