Other than amitriptyline, few antidepressants have shown consistent efficacy in migraine treatment prophylaxis. Only one other case supporting the use of mirtazapine for migraine prophylaxis has been reported. To our knowledge, there are no reports suggesting dose dependence in mirtazapine effectiveness for migraine treatment, nor proposals to explain the mechanism of this effect. A 25-year-old patient was followed in our outpatient department for DSM-IV treatment-resistant recurrent major depression. Multiple antidepressants were used and discontinued because of migraine exacerbation. Mirtazapine was then initiated for residual depressive symptoms. Decreased frequency and intensity of migraines were observed with low-dose mirtazapine, which reoccurred with higher doses. Migraine treatment with mirtazapine can be explained through two possible mechanisms. First, mirtazapine prevents migraine initiation through histamine and 5-HT(2) receptor family inhibition. Second, it treats migraines through 5-HT(1) receptor family activation. However, at higher doses, histamine activation may explain reoccurrence of migraines.