Background: This post hoc analysis evaluated the efficacy of eptinezumab vs placebo across 24 weeks of treatment in the placebo-controlled period of the DELIVER study in subgroups defined by prior treatment failure. Methods: DELIVER (NCT04418765) randomized adults with migraine to eptinezumab 100 mg, 300 mg, or placebo intravenous infusion every 12 weeks. Eligible patients needed documented evidence of 2–4 prior preventive treatment failures within the past 10 years. This post hoc analysis focused on subgroups of patients with prior treatment failure on topiramate, beta blockers, amitriptyline, and/or flunarizine. Results: The full analysis set included 890 patients: 633 previously failed topiramate, 538 failed beta blockers, 508 failed amitriptyline, and 333 failed flunarizine; within each subgroup, most patients had 2 prior treatment failures (51–56%). Across Weeks 1–12 in all subgroups, patients treated with eptinezumab experienced greater reductions from baseline in MMDs than those receiving placebo, with larger reductions observed over Weeks 13–24. Similarly, ≥50% MRRs were higher with eptinezumab than with placebo and increased following a second infusion. Conclusions: Eptinezumab demonstrated greater reductions in MMDs compared with placebo across all subgroups of prior preventive treatment failure, with evidence to suggest that a second dose provides additional benefit.