Objective To identify predictors of secondary headache in children consulting at the pediatric emergency department (ED) for headache with a focal neurologic deficit. Study design In this prospective cohort study, we enrolled children aged 6-18 years presenting to the ED of a tertiary care hospital with moderate to severe headache and focal neurologic deficit. Enrollment took place between March 2009 and February 2012. Children with a history of trauma, fever, or neurosurgical intervention were excluded from the study. The final diagnosis was made after 1 year of follow-up. Our primary aim was to identify any differences in the frequency of clinical signs between children with a final diagnosis of primary headache and those with a final diagnosis of secondary headache. Results Of the 101 patients included in the study, 66% received a final diagnosis of primary headache (94% migraine with aura), and 34% received a final diagnosis of secondary headache (76.5% focal epilepsy). On multivariate analysis, children with bilateral localization of pain had a higher likelihood (aOR, 8.6; 95% CI, 3.2-23.2; P < .001) of having secondary headache. Conclusion Among children presenting to the ED with focal neurologic deficits, a bilateral headache location was associated with higher odds of having a secondary cause of headache. Additional longitudinal studies are needed to investigate whether our data can aid management in the ED setting.