Dexamethasone, metoclopramide, ketorolac, and chlorpromazine have been used for the treatment of migraine headache. However, the effectiveness of these drugs in pain relief and prevention of recurrence and their side effects have not been compared yet. This was a randomized, double-blind clinical trial. Subjects were randomized to four groups; each received one of the following drugs intravenously: dexamethasone 8mg, ketorolac 30mg, metoclopramide 10mg, and chlorpromazine 25mg. The severity of headache in the two groups was assessed at starting point, 1h and 24h after the administration of drug using the visual analogue scale (VAS) on a scale of 0 to 10. No significant difference was found in the severity of symptoms between the four study groups before treatment, 1h, and 24h after treatment. The effect of all mentioned drugs on acute migraine headache was statistically significant at 1 and 24h post-treatment compared to baseline. No significant difference was detected in the number of unresponsive cases between the four groups. There was a trend toward higher effectiveness of dexamethasone in prevention of recurrence (P = 0.05). Side effects were more common in chlorpromazine and less common in the dexamethasone-treated patients (P < 0.001). The present clinical trial shows the effectiveness of dexamethasone in prevention of recurrence and low frequency of treatment side effects.