Objective To demonstrate that calcitonin gene–related peptide (CGRP) induces headache exacerbation with migraine‐like features in patients with persistent post‐traumatic headache (PTH) attributed to mild traumatic brain injury (TBI). Methods A randomized, double‐blind, placebo‐controlled, two‐way crossover study was conducted. Analyses were intention‐to‐treat. Eligible patients were aged 18 to 65 years and had a history of persistent PTH after mild TBI for at least 12 months. Patients were randomized to receive an intravenous infusion of 1.5μg/min of CGRP or placebo (isotonic saline) over 20 minutes on two separate experimental days. A 12‐hour observational period was used to evaluate the following outcomes: (1) difference in incidence of headache exacerbation with migraine‐like features and (2) difference in area under the curve for headache intensity scores. Results Thirty patients (mean age = 37 years, 25 women 83%) were randomized and completed the study. During the 12‐hour observational period, 21 of 30 patients (70%) developed headache exacerbation with migraine‐like features after CGRP, compared with 6 patients (20%) after placebo (p < 0.001). The baseline‐corrected area under the curve for headache intensity scores was significantly larger after CGRP, compared with placebo (p < 0.001). Interpretation Patients with persistent PTH are hypersensitive to CGRP, which underscores its pathophysiological importance. Furthermore, CGRP‐targeted therapies might provide a novel mechanism‐based treatment option for patients with persistent PTH. ANN NEUROL 2020;88:1220–1228