Objective: To assess the efficacy and safety of lasmiditan in the acute treatment of migraine. Methods: Adult patients with migraine were randomized (1:1:1) to a double-blind dose of oral lasmiditan 200 mg, lasmiditan 100 mg, or placebo, and were asked to treat their next migraine attack within 4 hours of onset. Over 48 hours following dosing, patients used an electronic diary to record headache pain, and also the presence of nausea, phonophobia, and photophobia, one of which was designated their most bothersome symptom (MBS). Results: Of the 1,856 patients who treated an attack, 77.9% had ≥1 cardiovascular risk factor in addition to migraine. Compared with placebo, more patients dosed with lasmiditan 200 mg were free from headache pain at 2 hours after dosing (32.2% vs 15.3%; odds ratio [95% confidence interval]: 2.6 [2.0, 3.6]; p<0.001); and similarly for lasmiditan 100 mg (28.2%; 2.2 [1.6, 3.0]; p<0.001). Furthermore, compared with placebo, more patients dosed with lasmiditan 200 mg (40.7% vs 29.5%; 1.6 [1.3, 2.1]; p<0.001), and lasmiditan 100 mg (40.9%; 1.7 [1.3, 2.2]; p<0.001), were free from their MBS at 2 hours after dosing. Adverse events were mostly mild or moderate in intensity. Conclusions: Lasmiditan, dosed at 200 mg and 100 mg, was efficacious and well tolerated in the treatment of acute migraine among patients with a high level of cardiovascular risk factors.