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Data are scarce on both stroke incidence rates and outcomes in Greece and in rural areas in particular. We performed a prospective population-based study evaluating the incidence of first-ever stroke in the Evros prefecture, a region of a total 147 947 residents located in North Eastern Greece.Adult patients with first-ever stroke were registered during a 24-month period (2010–2012) and followed up for 12 months. To compare our stroke incidence with that observed in other studies, we standardized our incidence rate data according to the European Standard Population, World Health Organization, and Segi population. We also applied criteria of data quality proposed by the Monitoring Trends and Determinants in Cardiovascular Disease project. Stroke diagnosis and classification were performed using World Health Organization criteria on the basis of neuroimaging and autopsy data.We prospectively documented 703 stroke cases (mean age: 75±12 years; 52.8% men; ischemic stroke: 80.8%; intracerebral hemorrhage: 11.8%; subarachnoid hemorrhage: 4.4%; undefined: 3.0%) with a total follow-up time of 119 805 person-years. The unadjusted and European Standard Population–adjusted incidences of all strokes were 586.8 (95% confidence interval [CI], 543.4–630.2) and 534.1 (95% CI, 494.6–573.6) per 100 000 person-years, respectively. The unadjusted incidence rates for ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage were 474.1 (95% CI, 435–513), 69.3 (95% CI, 54–84), and 25.9 (95% CI, 17–35) per 100 000 person-years, respectively. The corresponding European Standard Population–adjusted incidence rates per 100 000 person-years were 425.9 (95% CI, 390.9–460.9), 63.3 (95% CI, 49.7–76.9), and 25.8 (95% CI, 16.7–34.9) for ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage, respectively. The overall 28-day case fatality rate was 21.3% (95% CI, 18.3%–24.4%) for all strokes and was higher in hemorrhagic strokes than ischemic stroke (40.4%, 95% CI, 31.3%–49.4% versus 16.2%, 95% CI, 13.2%–19.2%).This is the largest to date population-based study in Greece documenting one of the highest stroke incidences ever reported in South Europe, highlighting the need for efficient stroke prevention and treatment strategies in Northeastern Greece.