Headache is a very common medical complaint. Four to six percent of the population will have a debilitating headache in their lifetime; and 1-2% of all Emergency Department (ED) visits involve patients with headaches. Although promethazine is used frequently, it has never been studied as a single-agent treatment in undifferentiated headache. We hypothesized that promethazine would be superior to prochlorperazine in the treatment of headache. We conducted a prospective, double-blinded, randomized, controlled trial on patients presenting to our ED between May and August 2005 with a chief complaint of headache. Each subject was randomized to receive either intravenous promethazine 25 mg or prochlorperazine 10 mg, and graded the intensity of their headache on serial 100-mm visual analog scales (VAS). Patients with dystonic reactions or akathesia were treated with diphenhydramine. Adequate pain relief was defined as an absolute decrease in VAS score of 25 mm. After discharge from the ED, patients were queried regarding the recurrence of headache symptoms, the need for additional pain medications, and the occurrence of any side effects since discharge. Thirty-five patients were enrolled in each group. Both drugs were shown to be effective in treatment of headaches. Prochlorperazine provided a faster rate of pain resolution and less drowsiness when compared to promethazine. Both medications were individually effective as abortive therapy for headache. Prochlorperazine was superior to promethazine in the rate of headache reduction and rate of home drowsiness, with similar rates of akathesia, nausea resolution, patient satisfaction, and headache recurrence within 5 days of discharge.