Purpose To assess the ability of convolutional neural networks (CNNs) to enable high-performance automated binary classification of chest radiographs. Materials and Methods In a retrospective study, 216 431 frontal chest radiographs obtained between 1998 and 2012 were procured, along with associated text reports and a prospective label from the attending radiologist. This data set was used to train CNNs to classify chest radiographs as normal or abnormal before evaluation on a held-out set of 533 images hand-labeled by expert radiologists. The effects of development set size, training set size, initialization strategy, and network architecture on end performance were assessed by using standard binary classification metrics; detailed error analysis, including visualization of CNN activations, was also performed. Results Average area under the receiver operating characteristic curve (AUC) was 0.96 for a CNN trained with 200 000 images. This AUC value was greater than that observed when the same model was trained with 2000 images (AUC = 0.84, P < .005) but was not significantly different from that observed when the model was trained with 20 000 images (AUC = 0.95, P > .05). Averaging the CNN output score with the binary prospective label yielded the best-performing classifier, with an AUC of 0.98 (P < .005). Analysis of specific radiographs revealed that the model was heavily influenced by clinically relevant spatial regions but did not reliably generalize beyond thoracic disease. Conclusion CNNs trained with a modestly sized collection of prospectively labeled chest radiographs achieved high diagnostic performance in the classification of chest radiographs as normal or abnormal; this function may be useful for automated prioritization of abnormal chest radiographs. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by van Ginneken in this issue.