Objective: To evaluate the efficacy and safety of eptinezumab, a humanized anti–calcitonin gene-related peptide monoclonal antibody, in the preventive treatment of chronic migraine (CM). Methods: The PRevention Of Migraine via Intravenous ALD403 Safety and Efficacy–2 (PROMISE-2) study was a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Adults with CM were randomly assigned to receive intravenous (IV) eptinezumab 100 mg, eptinezumab 300 mg, or placebo, administered on day 0 and week 12. The primary endpoint was change from baseline in mean monthly migraine days (MMDs) over weeks 1–12. Results: Among treated participants (n = 1072), baseline mean MMDs was ~16.1 across groups. Treatment with eptinezumab 100 mg and 300 mg was associated with significant reductions in MMDs across weeks 1–12 compared with placebo (placebo, −5.6, 100 mg, −7.7, p < 0.0001 vs placebo; 300 mg, −8.2, p < 0.0001 vs placebo). Treatment-emergent adverse events (TEAEs) were reported by 43.5% (100 mg), 52.0% (300 mg), and 46.7% (placebo) of patients. Nasopharyngitis was the only TEAE reported for >2% of eptinezumab treated patients at an incidence of greater than 2% over placebo; it occurred in the 300 mg eptinezumab arm (eptinezumab 9.4%, placebo 6.0%). Conclusion: In patients with CM, eptinezumab 100 mg and 300 mg was associated with a significant reduction in MMDs from the day following IV administration through week 12, was well tolerated, and demonstrated an acceptable safety profile.