Forty-eight patients with chronic daily headache, unresponsive to several combinations of pharmacological treatments, were selected for an open-label study using paroxetine. Patients were given 10 mg to 50 mg of paroxetine for a period of 3 to 9 months. Ninety-two percent of the patients improved significantly, based on the patients' percent of the reduction in number of headache days per month. The common side effects were fatigue, insomnia, and urogenital disturbances. The possible mechanism of action of paroxetine in the treatment of chronic daily headache is discussed. Paroxetine appears to be effective in the treatment of chronic daily headache; however, double blind studies are needed to confirm these preliminary findings.