OBJECTIVES To evaluate the substances associated with medication overuse headache (MOH) in a headache center, over the course of the past 15 years. BACKGROUND The acute treatment of migraine has substantially changed over the past 15 years, and therefore, the substances associated with MOH may have changed as well. METHODS We randomly reviewed charts of subjects seen during the years of 2005, 2000, 1995, and 1990, to identify substances associated with MOH. Since the criteria proposed by the second edition of the International Classification of Headache Disorders require causal attribution, demonstrated by improvement after withdrawal (and this was not assessed in this study), herein we refer to probable MOH (PMOH). We contrasted the substances associated with PMOH over the studied years. RESULTS Our sample consists of 1200 individuals, 300 per year of interest. The proportions of subjects with a diagnosis of PMOH remained stable over the years, varying from 64% of all cases seen in the center in 1990, to 59.3% in 2005. We found a significant decrease in the relative frequency of probable ergotamine overuse headache (from 18.6% to 0%, P < .0001), and in probable combination analgesic overuse headache (from 42.2% to 13.6%, P < .0001). The differences were not significant for opioid overuse headache. The relative frequency increased significantly for the triptans (from 0% to 21.6%, P < .0001), simple analgesics (from 8.8% to 31.8%, P < .05), and for combinations of acute medications (from 9.8% to 22.7%, P = .01). CONCLUSION While overuse of acute medications remains an important problem in the tertiary care arena, the substances associated with the overuse have dramatically changed over the past 15 years. Educational initiatives should emphasize that the newer specific acute migraine medications (triptans) may also be associated with PMOH.