Background: This post hoc analysis of the PROMISE-2 data provides an assessment of the total preventive migraine efficacy of eptinezumab over 24 weeks in patients with a dual diagnosis of chronic migraine (CM) and medication overuse headache (MOH). Methods: PROMISE-2 was a double-blind, placebo-controlled, phase 3 study of eptinezumab (NCT02974153) over 24 weeks. Endpoints analyzed here include changes in MMDs, changes in monthly days of AHM use (total and class-specific), percentage of patients below thresholds for CM and MOH, and assessments patient-reported outcomes (PROs). Results: 40.2% patients with CM also had a diagnosis of MOH at baseline. Mean changes from baseline in MMDs during Weeks 1–12 were -8.4 and -8.6 in eptinezumab 100 mg and 300 mg treatment groups, respectively (vs 16.7 at baseline), compared with -5.4 in the placebo group (P<0.0001 vs placebo for both doses). Total monthly AHM use also decreased with eptinezumab. For all 24 weeks, 51.1% (100 mg) and 54.4% (300 mg) of eptinezumab-treated patients were below the ICHD thresholds for diagnosis of CM, compared with 32.4% of patients receiving placebo. Conclusions: This subgroup analysis of patients with a dual diagnosis of CM and MOH suggests that eptinezumab treatment resulted in greater improvements overall compared with placebo.