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Background: KRAS mutation can alter the treatment plan after resection of colorectal cancer. Despite its importance, the KRAS status of several patients remains unchecked because of the high cost and limited resources. This study developed a deep neural network (DNN) to predict the KRAS genotype using hematoxylin and eosin (H&E)-stained histopathological images., Study Design: Three DNNs were created (KRAS&#95;Mob, KRAS&#95;Shuff, and KRAS&#95;Ince) using the structural backbone of the MobileNet, ShuffleNet, and Inception networks, respectively. The Cancer Genome Atlas was screened to extract 49,684 image tiles that were used for deep learning and internal validation. An independent cohort of 43,032 image tiles was used for external validation. The performance was compared with humans, and a virtual cost-saving analysis was done., Results: The KRAS&#95;Mob network (area under the receiver operating curve [AUC] 0.8, 95% CI 0.71 to 0.89) was the best-performing model for predicting the KRAS genotype, followed by the KRAS&#95;Shuff (AUC 0.73, 95% CI 0.62 to 0.84) and KRAS&#95;Ince (AUC 0.71, 95% CI 0.6 to 0.82) networks. Combing the KRAS&#95;Mob and KRAS&#95;Shuff networks as a double prediction approach showed improved performance. KRAS&#95;Mob network accuracy surpassed that of two independent pathologists (AUC 0.79 [95% CI 0.64 to 0.93], 0.51 [95% CI 0.34 to 0.69], and 0.51 (95% CI 0.34 to 0.69]; p < 0.001 for all comparisons)., Conclusion: The DNN has the potential to predict the KRAS genotype directly from H&E-stained histopathological slide images. As an algorithmic screening method to prioritize patients for laboratory confirmation, such a model might possibly reduce the number of patients screened, resulting in significant test-related time and economic savings., (Copyright © 2022 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)