ABSTRACT: Background Patients with large vessel occlusion stroke (LVOS) need to be rapidly identified and transferred to comprehensive stroke centers. However, current prehospital evaluation and strategies still remain challenging. Methods and Results We retrospectively reviewed our prospectively collected database of patients with acute ischemic stroke (AIS). Based on the items of National Institutes of Health Stroke Scale and medical history that had a strong association with LVOS, we designed the 4-item Stroke Scale (4I-SS) and validated it in multi-centers. The 4I-SS incorporated gaze, level of consciousness, arm weakness, and atrial fibrillation. Receiver operating characteristic analysis was used to compare the 4I-SS with previously established prehospital prediction scales. Finally, 1630 and 11 440 patients were included in the derivation and validation cohort, respectively. In the validation cohort, Youden Index, area under the curve, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the 4I-SS≥4 to predict LVOS were 0.494, 0.800, 0.657, 0.837, 0.600, 0.868, and 0.788, respectively, and that of the 4I-SS≥7 to predict basilar artery occlusion were 0.200, 0.669, 0.229, 0.971, 0.066, 0.974, and 0.899, respectively. Youden Index and area under the curve were higher than previously published scales for predicting LVOS. Further analysis showed that for predicting whether cardiogenic embolism was the cause, its accuracy was 0.922 when the 4I-SS score, including atrial fibrillation, was ≥6, and its accuracy of predicting the occluded vessel was intracranial internal carotid artery or M1 segment of the middle cerebral artery when it was ≥7 was 0.590. Conclusions The 4I-SS is an effective and simple tool that can identify LVOS and its cause. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03317639.