Background: In Spain, stroke is a major public health concern, but large population-based studies are scarce and date from the 1990s. We estimated the incidence and in-hospital mortality of stroke through a multicentered population-based stroke register in 5 geographical areas of Spain, i.e. Lugo, Almería, Segovia, Talavera de la Reina and Mallorca, representing north, south, central (×2) and Mediterranean areas of Spain, respectively, the aim and novelty being that all methodologies were standardized, and diagnoses were verified by a neurologist using neuroimaging techniques. Methods: The register identified subjects >17 years of age who suffered a first-ever stroke or transient ischemic attack (TIA) between 1 January and 31 December 2006. Stroke and TIA were defined according to the WHO criteria. The Lausanne Stroke Registry definitions were used to classify ischemic stroke subtypes, as follows: (1) large-artery atherosclerosis (LAA); (2) cardioembolism (CE); (3) lacunar stroke or small-artery occlusion (SAO); (4) stroke of other infrequent cause (SIC), and (5) stroke of undetermined cause (UND). We used several complementary data sources such as hospital discharge registers, emergency room registers and primary care surveillance systems. Results: In the 1-year study period, we identified 2,700 first-ever cerebrovascular episodes (53% men; 2,257 strokes + 443 TIA episodes). Brain CT in the acute stage was performed in 99% of cases. Of a total of 2,257 stroke patients, 1,817 (81%) had cerebral infarction, 350 (16%) had intracerebral hemorrhage, 59 (3%) had subarachnoid hemorrhage (SAH) and 31 (1%) had unclassifiable stroke. The overall unadjusted annual incidence for all cerebrovascular events was 187 per 100,000 [95% confidence interval (CI) 180–194; incidence for men: 202, 95% CI 189–210; incidence for women: 187, 95% CI 180–194]. The subtype of ischemic stroke could be determined in 1,779 patients and was classified as LAA in 624 (35%), CE in 352 (20%), SAO in 316 (18%), SIC in 56 (3%) and UND in 431 (24%). The incidence rates per 100,000 (95% CI) standardized to the 2006 European population were as follows: all cerebrovascular events, 176 (169–182); all stroke (non-TIA), 147 (140–153); TIA, 29 (26–32); ischemic stroke, 118 (112–123); intracerebral hemorrhage, 23 (21–26), and SAH, 4.2 (3.1–5.2). Incidence rates clearly increased with age in both genders, with a peak at or above 85 years of age. The in-hospital mortality was 14%. Conclusions: Our results show that the incidence of stroke and TIA in Spain is moderate compared to other Western and European countries. However, it is expected that these figures will change due to progressively aging populations.