Background Computed tomography is the most frequently used imaging modality in acute stroke imaging protocols. Detection of small volume infarcts in the brain and cardioembolic sources of stroke is difficult with current computed tomography protocols. Furthermore, the role of computed tomography findings to predict recurrent ischemic stroke is unclear. With ENCLOSE, we aim to improve (1) the detection of small volume infarcts with thin slice computed tomography perfusion (CTP) images and thromboembolic source with cardiac computed tomography techniques in the acute stage of ischemic stroke and (2) prediction of recurrent ischemic stroke with computed tomography-derived predictors. Methods/design: ENCLOSE is a prospective multicenter observational cohort study, which will be conducted in three Dutch stroke centers (ClinicalTrials.gov Identifier: NCT04019483). Patients (≥18 years) with suspected acute ischemic stroke who undergo computed tomography imaging within 9 h after symptom onset are eligible. Computed tomography imaging includes non-contrast CT, CTP, and computed tomography angiography (CTA) from base of the heart to the top of the brain. Dual-energy CT data will be acquired when possible, and thin-slice CTP reconstructions will be obtained in addition to standard 5 mm CTP data. CTP data will be processed with commercially available software and locally developed model-based methods. The post-processed thin-slice CTP images will be compared to the standard CTP images and to magnetic resonance diffusion-weighted imaging performed within 48 h after admission. Detection of cardioembolic sources of stroke will be evaluated on the CTA images. Recurrence will be evaluated 90 days and two years after the index event. The added value of imaging findings to prognostic models for recurrent ischemic stroke will be evaluated. Conclusion The aim of ENCLOSE is to improve early detection of small volume stroke and thromboembolic sources and to improve prediction of recurrence in patients with acute ischemic stroke.