Aim and Methods: Erenumab and galcanezumab have shown great results for migraine prevention in several clinical trials. However, strict inclusion criteria, absence of concomitant medication and selective outcome report may sometimes be barely representative of the real-world daily practice. Therefore, this observational, retrospective, non-comparative study was aimed to evaluate the effectiveness and safety of erenumab 140 mg and galcanezumab 120 mg in real-world patients with difficult-to-treat episodic or chronic migraine, who previously did not respond to up to three well-stablished pharmacological alternatives for migraine prevention. A combination of objective well-defined tools and vastly used patient reported outcome measurements were evaluated at baseline and after the administration of 3 and 6 doses. Results: from 180 patients, 142 matched inclusion criteria for the present study. Data here reported shows that erenumab and galcanezumab reduced mean headache days, acute migraine specific medication days, Headache Impact Test score, Migraine Disability Assessment Test score and Visual Analogue Scale score after 3 and 6 doses in real-world patients diagnosed with difficult to treat chronic or episodic migraine (p<0.01). Moreover, acute migraine specific medication days were reduced by a half in, at least, a 50% of the patients enrolled in each of the groups of the study. Both treatments exhibited a great safety profile, rarely leading to discontinuation because of poor tolerance. Conclusions: Erenumab and galcanezumab seem effective and well tolerated for migraine prevention in real-world patients with episodic or chronic migraine who previously failed to oral preventive therapies.