Antidepressants are used to treat chronic daily headache disorders such as migraine and chronic tension-type headache (TTH), which are often associated with depression and anxiety. Here, we studied the efficacy and tolerability of amitriptyline and citalopram, given alone or in combination, in patients with 'triple' comorbidity of depression, TTH, and migraine. Eighty-eight patients were enrolled in the study and randomly divided into two groups. The first group received amitriptyline and the second citalopram for 16 weeks. Patients were assessed at weeks 0, 4, 8, and 16. The two drugs were equally efficacious in relieving depressive symptoms, although amitriptyline was more efficacious than citalopram in reducing migraine and TTH attacks. Patients who did not respond to monotherapy (<30% of improvement in the clinical scores) were treated with a combination of the two drugs for 16 additional weeks. In these selected patients, the combined treatment produced a substantial improvement in depression, migraine and TTH without producing major side effects such as those commonly related to the 'serotonergic' syndrome. The results indicate that a combined therapy with amitriptyline and citalopram may be particularly beneficial for patients with TTH, migraine and comorbid depression that do not respond to monotherapy.