Background and Purpose— The timely diagnosis of stroke at the initial examination is extremely important given the disease morbidity and narrow time window for intervention. The goal of this study was to develop a supervised learning method to recognize acute cerebral ischemia (ACI) and differentiate that from stroke mimics in an emergency setting. Methods— Consecutive patients presenting to the emergency department with stroke-like symptoms, within 4.5 hours of symptoms onset, in 2 tertiary care stroke centers were randomized for inclusion in the model. We developed an artificial neural network (ANN) model. The learning algorithm was based on backpropagation. To validate the model, we used a 10-fold cross-validation method. Results— A total of 260 patients (equal number of stroke mimics and ACIs) were enrolled for the development and validation of our ANN model. Our analysis indicated that the average sensitivity and specificity of ANN for the diagnosis of ACI based on the 10-fold cross-validation analysis was 80.0% (95% confidence interval, 71.8–86.3) and 86.2% (95% confidence interval, 78.7–91.4), respectively. The median precision of ANN for the diagnosis of ACI was 92% (95% confidence interval, 88.7–95.3). Conclusions— Our results show that ANN can be an effective tool for the recognition of ACI and differentiation of ACI from stroke mimics at the initial examination.