Previous uncontrolled, nonrandomized trials suggest that magnesium sulfate (MgSO4) is effective in the treatment of headache. The objective of this study was to determine the efficacy of MgSO4 vs. prochlorperazine in emergency department (ED) patients with acute headache. Patients presenting to the ED with a chief complaint of headache who met study criteria were enrolled. Each patient rated pain on a visual analog scale before and 30 min after a randomized study drug infusion. Thirty-six similar patients were enrolled. There was complete or partial pain relief in 90% of the prochlorperazine group and 56% of the MgSO4 group, a statistically significant difference. Prochlorperazine caused significantly fewer side effects, and none of the patients required additional medication during the study period. It was determined that intravenous prochlorperazine is highly effective in the treatment of headache and magnesium is moderately effective. Response to MgSO4 was unrelated to serum Mg level.