Background Fremanezumab is an anti-calcitonin gene-related peptide monoclonal antibody efficacious for chronic migraine prophylaxis. We evaluated real-world prophylactic efficacy of fremanezumab for refractory and resistant chronic migraine in a United Kingdom specialist headache centre (Hull Migraine Clinic). Materials and Methods 289 adult patients with resistant and refractory chronic migraine commenced fremanezumab with prospective follow-up, maintaining headache diaries for ≥1-month pre-fremanezumab initiation and continuously thereafter. Patients failed 6 median previous prophylactics. We measured monthly headache days, migraine days, headache-free days, analgesia medication days, triptan days and Headache Impact Test-6 scores at baseline and during treatment. Results All outcomes significantly improved in results of 182 patients at 4-month follow-up (p<0.0001), with reduced median monthly headache days (by 9 days), migraine days (by 10 days) and Headache Impact Test-6 (by 14.5 points). 80% patients achieved ≥30% migraine reduction, whilst 68% and 42% patients achieved >50% and >75% reduction. 58%, 39% and 17% patients achieved ≥30%, >50% and >75% headache day reduction. OnabotulinumtoxinA-unresponsive patients exhibited substantial responses, with 78%, 66% and 39% patients achieving ≥30%, >50% and >75% migraine reduction. Medication-overuse did not affect responses. 45% patients achieved <15 headache days in any month, and 65% achieved <8 migraine days in any month. 37% achieved both outcomes. In multivariate analyses, baseline headache-freedom and lower Headache Impact Test-6 score associated with ≥30% migraine reduction (p<0.05), whilst baseline headache-freedom and lower migraine-days associated with achieving <15 headache days in any month (p<0.01). Conclusion Fremanezumab demonstrates real-world efficacy at 4 months in resistant and refractorychronic migraine, including in OnabotulinumtoxinA-unresponsive patients, irrespective of medication-overuse. Baseline headache-freedom, lower migrainedays and lower Headache Impact Test-6 score heralded superior responses.