Many patients with severe migraine remain refractory to the current treatment regimens or cannot tolerate the side effects. Since current research implicates serotonin dysregulation in migraine pathogenesis, we investigated in a double blind, placebo controlled study the prophylactic effect of the serotonergic drug fluoxetine. Sixteen subjects were randomly assigned to 8 week fluoxetine treatment and 16 to the placebo group; nine subjects in each group completed the study. Migraine headache scores were obtained for two weeks prior to commencement of treatment, and then for each successive two week period. Zung depression scores were obtained before and after completion of the study. Fluoxetine caused significant reduction in headache scores starting with weeks 3-4 of treatment; there was no significant change with placebo. Depression scores did not differ between groups before treatment, and did not significantly change with either treatment. Fluoxetine appears to be a safe and effective drug for migraine prophylaxis, and deserves further therapeutic trials with larger groups for longer periods of time.