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Introduction: Monoclonal antibodies against calcitonin gene-related peptide (CGRP) have revolutionized migraine treatment, though one-third of patients do not respond to these medications. One of the emergent reasons for this apparent lack of response could be a wearing-off effect, as the case of our patient illustrates. Clinical Case: A woman aged 36 years with the diagnosis of migraine with aura since childhood, which transforms to chronic migraine and daily headache, with analgesic overuse for the past 5 years. She failed to respond to multiple oral preventatives, botulinum toxin, and two CGRP antibodies (erenumab and galcanezumab). After initiating quarterly eptinezumab, she noticed a relevant improvement in the number of headache days per month for the first 8 weeks but experienced a clear wearing-off effect during the third month of treatment, for two consecutive treatments. We altered administration to every 8 weeks, which better controlled her migraine frequency. Conclusions: CGRP antibodies can show a wearing-off effect, which should be identified in order to plan individualized treatment and avoid an incorrect interpretation as therapeutic failure. Our case also shows that patients with chronic migraine refractory to two antibodies can respond to a third CGRP antibody, in this case, intravenous eptinezumab.