Objective: To assess the safety and efficacy of AMG 301, an inhibitor of the pituitary adenylate cyclase-activating polypeptide (PACAP)-1 (PAC1) receptor, for prevention of migraine. Methods: In a double-blind trial, patients were randomized 4:3:3 to placebo, AMG 301 210 mg every 4 weeks, or AMG 301 420 mg every 2 weeks for 12 weeks. Effect on monthly migraine days and other secondary measures were assessed over weeks 9–12. Safety and tolerability were assessed. Results: Of 343 randomized patients (mean age, 41.8–42.5 years), the majority were women (85.4–90.4%), white (94.1–96.2%), and had episodic migraine (62.5–67.9%). A total of 305 patients completed treatment (placebo, n = 124; AMG 301 210 mg, n = 94; AMG 301 420 mg, n = 87). Least squares mean reduction at week 12 in monthly migraine days from baseline was −2.5 (0.4) days for placebo and −2.2 (0.5) days for both AMG 301 treatment groups. No difference between AMG 301 and placebo on any measure of efficacy was observed; mean (95% confidence interval) treatment difference versus placebo for monthly migraine days for AMG 301 210 mg, 0.3 (−0.9 to 1.4); AMG 301 420 mg, 0.3 (−0.9 to 1.4). The incidence of adverse events was similar across groups. Conclusion: AMG 301 offered no benefit over placebo for migraine prevention; further studies may be necessary to fully understand the role of PACAP isoforms and its receptors in migraine pathophysiology. Study Registration: ClinicalTrials.gov: NCT03238781