Medication overuse is relatively common in patients with frequent headache. To explore the prevalence of patients who meet the criteria for substance dependence in Diagnostic and Statistical Manual of Mental Disorders, Edition IV (DSM-IV), and to identify variables of substance dependence among patients with chronic daily headache, we recruited consecutive patients with chronic daily headache at a headache clinic from November 1999 to June 2004. Each patient completed a headache intake form, a dependence questionnaire modified from DSM-IV, and the Hospital Anxiety and Depression Scale (HADS). The presence of probable medication overuse headache (pMOH) was defined on the basis of the International Classification of Headache Disorders, 2nd edition, 2004. A total of 1,861 patients with chronic daily headache (1,369 women, 492 men; mean age, 49.6+/-15.4 years) were recruited. Almost half (895/1,861, 48%) met criteria of pMOH, and 606 of these patients (606/895, 68%) met three of five DSM-IV substance dependence criteria. In contrast, only 191 of 968 patients without pMOH (20%) met the DSM-IV criteria (OR=8.6, [7.0-10.6], chi-square test, P<0.001). Patients who fulfilled DSM-IV criteria of dependence had higher numbers of physician appointments in the past year. Multivariate logistic regression analyses revealed that migraine headache, frequent physician consultation, intensity of headache, and presence of a higher anxiety score were significant independent variables for substance dependence. Among patients with chronic daily headache, pMOH was associated with behaviors of substance dependence.