Our aim was to study and compare pharmacoepidemiology of headache treatment in two different settings: inside and outside a specialized Centre. We analysed the differences in headache treatment between 612 subjects admitted for the first visit (‘naive’) (F/M: 2.41; mean age = 37.31 ± 14.09 years) and 620 subjects admitted for a control visit (F/M: 3.18; mean age = 44.30 ± 15.37 years) to the Headache Centre of the University of Modena and Reggio Emilia. Most patients suffered from migraine. As acute treatment, on the first visit, 49.4% of them were taking drugs prescribed by a doctor; 41.5% were taking over-the-counter analgesics (OTCAs); 9.1% were not taking any drug. On the control visit, 81.3% of patients were taking prescription drugs; 15.8% OTCAs; 2.9% were not taking drugs (overall chi-square = 139.229, P < 0.001). Non-selective analgesics were the most-used drugs. Triptans were used by 9.1% of ‘naive’ patients and by 31.8% of patients attending for the control visit (Fisher's Z = 7.655, P < 0.001). Nimesulide was the most-used drug. A prophylactic treatment was made by 16.8% of ‘naive’ patients, and by 58.2% of patients admitted to the control visit (Fisher's Z = 12.135, P < 0.001). Antidepressants were the class of drugs most used for prophylaxis. Amitriptyline was the drug for prophylaxis most frequently used by patients attending the control visit, while flunarizine was the most frequently used by ‘naive’ patients. Before being examined in a specialized centre, few patients take prescription drugs, triptans, or prophylactic drugs; specialized care increases the proportion of patients taking prophylactic drugs, and changes the type of acute treatment used into disease-specific medication for headache.