The objective of this study was to determine the efficacy of nitrous oxide in the therapy of acute migraine symptoms in emergency department (ED) patients. This was a prospective, randomized, double blind study of patients presenting to an ED. All eligible patients had a prior diagnosis and symptoms consistent with migraine headache and a normal neurological examination. Patients were randomized to receive either 50% nitrous oxide and 50% oxygen or 100% oxygen over 20 minutes. All patients completed a visual analog pain scale before and immediately after intervention. Initial pain scores and change in pain scores between the two groups were compared. There were 22 patients enrolled, 10 in the nitrous oxide group and 12 in the oxygen group. The groups were similar in age, gender, duration of headache, and initial pain scores. Pain scores decreased significantly in the nitrous oxide group (median change, 69 to 21 mm, P = .02). The oxygen group did not show significant change in pain scores (median change, 78.5 to 72, P = .09). Eighty percent of patients receiving nitrous oxide required no rescue medication at the completion of the intervention, compared with 17% of those receiving 100% oxygen (P = .008). Twenty minutes after termination of intervention, 60% of patients who had received nitrous oxide still required no rescue medication, compared with 8% of those who had received 100% oxygen (P = .02). Nitrous oxide shows efficacy in ED short-term treatment of acute migraine headache.