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There is a lack of definitive pediatric literature on effective pharmacotherapy for persistent post-concussion headache symptoms. This study assessed whether acute metoclopramide treatment in the Emergency Department (ED) was associated with a reduction in persistent headache in children at 1- and 4-weeks post-concussion.Children aged 8–17 years with acute concussion presenting to 9-Canadian Pediatric EDs were enrolled in a prospective cohort study, from August 2013–June 2015. Primary and secondary outcomes were persistent headache at 1- and 4-week post-injury respectively. Headache persistence was based on the one and four-week headache scores minus recalled pre-injury score using the Post-Concussion Symptom Inventory. The association between metoclopramide and headache persistence at 1- and 4-weeks were examined using unadjusted and adjusted regression and 1:4 propensity score matching model.Baseline assessments were completed in 2095 participants; 65 (3.1%) received metoclopramide within 48-hours of injury. At 1- and 4-weeks, 54% (963/1808) and 26% (456/1780) of participants had persistent headache relative to baseline respectively. In unadjusted analysis, no association between metoclopramide and headache persistence at 1-week was found [treated vs. untreated: 1-week (53% vs. 53%; relative risk (RR) = 1.0 (95%CI: 0.8, 1.3); 4-weeks (27.3% vs. 25.6%; RR = 1.0 (95% CI: 0.9, 1.2)]. Metoclopramide was not associated with lower headache risk on propensity score matching [treated vs. untreated: 1-week, n = 220 (52% vs. 59.4%; RR = 0.8 (95%CI: 0.6, 1.2) and 4-weeks, n = 225 (27.1% vs. 32.8%; RR = 0.9 (95%CI: 0.8, 1.1)].Metoclopramide administration was not associated with a reduction in headache persistence in children seeking ED care due to a concussion. Further research is necessary to determine which pharmacotherapies may be effective for acute and persistent post-concussive headache.