The hospital-based stroke registry is useful for understanding the diverse clinical characteristics of stroke related to geographical, racial or environmental differences. The Khorasan Stroke Registry (KSR) was established for the evaluation of incidence, clinical manifestations, risk factors, topography and etiology of ischemic stroke in Southern Khorasan, Iran, during 2001-2005. Consecutive stroke patients underwent a standard battery of diagnostic investigations by a stroke neurologist. The topography and etiology of brain infarction were determined by the Practical Iranian Criteria classification. The incidence of ischemic stroke in the Persian population is 43.17 cases per 100,000 people per year. A total of 1,392 ischemic stroke patients (738 females, 654 males) were evaluated in the KSR. The etiologies included atherosclerosis (53.6%), followed by uncertain causes (19.9%), cardioembolism (11.8%) and miscellaneous etiologies (2.9%). Of our patients, 11.7% had both atherosclerosis and cardioembolic mechanisms. Rheumatic valvular disease was present in 44.8% of cardioembolic stroke patients and caused 4.31 preventable stroke cases per 100,000 Persian people per year. Hypertension and history of ischemic cerebrovascular events were the most frequent risk factors, 53.1 and 22.3%, respectively. The in-hospital mortality of our ischemic stroke patients was 7.3%. A total of 336 patients with intracerebral hemorrhage (189 females, 147 males) were evaluated in the KSR. The incidence of intracerebral hemorrhage in the Persian population is 10.43 cases per 100,000 people per year. The high frequency of atherosclerotic etiology in the KSR is due to its classification criteria, which do not separate small vessel territory infarcts as a different etiologic subtype. Rheumatic valvular disease is an important cause of stroke in the Persian population.