Background: Calcitonin gene-related peptide (CGRP) has recently been implicated in the pathogenesis of post-traumatic headache (PTH), which raises the prospect for therapeutic use of monoclonal antibodies targeting CGRP or its receptor. Therefore, we decided to assess the efficacy, tolerability, and safety of erenumab for prevention of persistent PTH attributed to mild traumatic brain injury. Methods: A single-center, non-randomized, single-arm, open-label study of erenumab for adults aged 18-65 years with persistent PTH. Patients were assigned to receive 140-mg erenumab monthly by two subcutaneous 1-mL injections, given every 4 weeks for 12 weeks. The primary outcome measure was the mean change in number of monthly headache days of moderate to severe intensity from baseline (4-week pretreatment period) to week 9 through 12. Tolerability and safety endpoints were adverse events (i.e. number and type). Results: Eighty-nine of 100 patients completed the open-label trial. At baseline, the mean monthly number of headache days of moderate to severe intensity was 15.7. By week 9 through 12, the number was reduced by 2.8 days. The most common adverse events were constipation (n = 30) and injection-site reactions (n = 15). Of 100 patients who received at least one dose of erenumab, two patients discontinued the treatment regimen due to adverse events. Conclusions: Among patients with persistent PTH, erenumab resulted in a lower frequency of moderate to severe headache days in this 12-week open-label trial. In addition, erenumab was well-tolerated as discontinuations due to adverse events were low. Placebo-controlled randomized clinical trials are needed to adequately evaluate the efficacy and safety of erenumab in patients with persistent PTH. Trial registration: ClinicalTrials.Gov, NCT03974360. Registered on April 17, 2019-Retrospectively registered