The exact relationship between depression and chronic headache remains unclear. Considerable clinical and pharmacological evidence suggests the existence of a common biological terrain. Many antidepressant drugs are effective in the treatment of migraine and chronic headache disorders. Ritanserin, a new very selective serotonin-2 (5-HT2) antagonist, has recently shown both analgesic and antidepressant properties. The present study compares in a double-blind design, the effectiveness of ritanserin and amitriptyline, a well-known antidepressant extensively used in migraine prophylaxis. Thirty-eight patients (30 females and 8 males ranging in age from 20 to 50 yrs) were classified according to the International Headache Society criteria as: patients with chronic tension-type headache (CTH) (11 cases) and patients with coexisting migraine and CTH (MCTH) (27 cases). Only patients with a score equal to or higher than 18 on the Hamilton Rating Scale for Depression (HRSD) were included. Ritanserin was highly effective in reducing Pain Total Index and analgesic consumption in chronic headache, and its activity was similar to that observed during amitriptyline treatment. A significant improvement of HRSD and HRSA (Hamilton Rating Scale for Anxiety) scores was observed during both treatments. The main results of our study concern the demonstration of antiheadache and antidepressive properties of ritanserin. To better define the profile of the patients and their clinical responsiveness to the treatment, dexamethasone suppression test, clonidine test and nociceptive flexion reflex were investigated in our patients. Our data confirm the usefulness of these methods as markers of chronic headache with depression.