Recently, a new nasal spray formulation of dihydroergotamine was developed which facilitates at-home treatment of migraine. We studied the efficacy, safety, and tolerability of dihydroergotamine nasal spray as monotherapy in the acute treatment of classic and common migraine in two, identical, double-blind, randomized, placebo-controlled trials. Of the 229 patients enrolled, 206 (102 dihydroergotamine nasal spray, 104 placebo) were included in the intent-to-treat analyses; 182 treated two headaches and 24 treated one headache. Based on both the patients' and physicians' ratings, dihydroergotamine nasal spray was significantly superior to placebo for reducing the severity of headache pain in both studies, and in relieving nausea in Study 2. The onset of significant efficacy with dihydroergotamine nasal spray compared to that with placebo for both severity of headache pain and relief of nausea occurred at I hour in Study 2 and at 3 hours in Study 1. Dihydroergotamine nasal spray was also significantly superior to placebo for the relief of headache pain in both studies. Based on the physicians' global evaluations of treatment efficacy for headache pain, 71% of the dihydroergotamine-treated patients in Study 2 and 59% of their counterparts in Study 1 were considered to be responders. The dihydroergotamine-treated patients had less newly-occurring vomiting than the placebo-treated patients. The majority of adverse events reported by the dihydroergotamine-treated patients were nasopharyngeal. The results demonstrate the efficacy, safety, and tolerability of dihydroergotamine nasal spray as monotherapy in the treatment of acute migraine attacks.