The correct diagnosis of headache disorders in an emergency room is important for developing early management strategies and determining optimal emergency room activities. This prospective clinical based study was performed in order to determine demographic and clinical clues for differential diagnosis of primary and secondary headache disorders and also to obtain a classification plot for the emergency room practitioners. This study included 174 patients older than 15 years of age presenting in the emergency room with a chief complaint of headache. Definite headache diagnoses were made according to ICHD-II criteria. Classification and regression tree was used as new method for the statistical analysis of the differential diagnostic process. Our 174 patients with headache were diagnosed as basically primary (72.9%) and secondary (27.1%) headaches. Univariate analysis with cross tabs showed three important results. First, unilateral pain location caused 1.431-fold increase in the primary headache risk (p = 0.006). Second, having any triggers caused 1.440-fold increase in the primary headache risk (p = 0.001). Third, having associated co-morbid medical disorders caused 4.643-fold increase in the secondary headache risk (p < 0.001). It was concluded that the presence of comorbidity, the patient's age, the existence of trigger and relaxing factors, the pain in other body parts that accompanies headache and the quality of pain in terms of location and duration were all important clues for physicians in making an accurate differentiation between primary and secondary headaches.