BACKGROUND Despite the benefits of antimigraine medications for patients with migraines, parenteral administration of these drugs has certain disadvantages for at-home patient use. OBJECTIVE To examine the safety and efficacy of an intranasal spray formulation of dihydroergotamine mesylate in the treatment of migraines. METHODS Double-blind, placebo-controlled trial in patients with migraines. METHODS Both private and institutional practice. METHODS A total of 348 patients with a diagnosis of migraine according to International Headache Society criteria were recruited; 310 patients qualified for participation. METHODS Patients self-administered either 2 mg of dihydroergotamine mesylate, 3 mg of dihydroergotamine mesylate, or a placebo for each of 2 moderate to severe migraine headaches using a nasal spray apparatus. METHODS Patients rated pain severity, functional ability, headache pain relief, incidence and severity of nausea, and the incidence of vomiting, photophobia, and phonophobia prior to treatment (base-line) and again at 0.5, 1, 2, 3, and 4 hours after treatment. Recurrences of headache pain within 24 hours were also noted. RESULTS Self-administration of dihydroergotamine resulted in significant increases in pain relief and functional ability and significant decreases in pain intensity and nausea compared with the placebo. Among patients treated with 2 mg of dihydroergotamine mesylate, 27% considered their migraine resolved (ie, no pain or mild pain) as early as 30 minutes after treatment. By 4 hours after treatment, 70% of these patients' headaches were resolved. Headache pain returned within 24 hours in only 14% of patients whose headaches had been resolved. No serious adverse effects of dihydroergotamine treatment were observed, and the adverse events that did occur were primarily related to the route of administration. The 2-mg dihydroergotamine mesylate dose provided slightly superior pain relief and was associated with fewer adverse events compared with the 3-mg dihydroergotamine mesylate dose. CONCLUSIONS The present results suggest that intranasal administration of dihydroergotamine represents an important new therapeutic option for migraine sufferers.