We performed a retrospective, observational study at a level I pediatric trauma center of children with moderate-to-severe traumatic brain injury (TBI) from January 2002 to September 2006 to identify clinical and radiographic risk factors for early post-traumatic seizures (EPTS). Two hundred and ninety-nine children ages 0-15 years were evaluated, with 24 excluded because they died before the initial head computed tomography (CT) was obtained (n=20), or because their medical records were missing (n=4). Records were reviewed for accident characteristics, pre-hospital hypoxia or hypotension, initial non-contrast head CT characteristics, seizure occurrence, antiepileptic drug (AED) administration, and outcome. All care was at the discretion of the treating physicians, including the use of AEDs and continuous electroencephalogram (EEG) monitoring in patients receiving neuromuscular blocking agents. The primary outcome was seizure activity during the first 7 days as determined by clinician observation or EEG analysis. Of the 275 patients included in the study, 34 had identified EPTS (12%). Risk factors identified on bivariable analysis included pre-hospital hypoxia, young age, non-accidental trauma (NAT), severe TBI, impact seizure, and subdural hemorrhage, while receiving an AED was protective. Independent risk factors identified by multivariable analysis were age <2 years (OR 3.0 [95% CI 1.0,8.6]), Glasgow Coma Scale (GCS) score ≤8 (OR 8.7 [95% CI 1.1,67.6]), and NAT as a mechanism of injury (OR 3.4 [95% CI 1.0,11.3]). AED treatment was protective against EPTS (OR 0.2 [95% CI 0.07,0.5]). Twenty-three (68%) patients developed EPTS within the first 12 h post-injury. This early peak in EPTS activity and demonstrated protective effect of AED administration in this cohort suggests that to evaluate the maximal potential benefit among patients at increased risk for EPTS, future research should be randomized and prospective, and should intervene during pre-trauma center care with initiation of continuous EEG monitoring as soon as possible.