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Background: Objective and early identification of hospitalized patients, and particularly those with novel coronavirus disease 2019 (COVID-19), who may require mechanical ventilation (MV) may aid in delivering timely treatment., Research Question: Can a transparent deep learning (DL) model predict the need for MV in hospitalized patients and those with COVID-19 up to 24 h in advance?, Study Design and Methods: We trained and externally validated a transparent DL algorithm to predict the future need for MV in hospitalized patients, including those with COVID-19, using commonly available data in electronic health records. Additionally, commonly used clinical criteria (heart rate, oxygen saturation, respiratory rate, Fio 2 , and pH) were used to assess future need for MV. Performance of the algorithm was evaluated using the area under receiver operating characteristic curve (AUC), sensitivity, specificity, and positive predictive value., Results: We obtained data from more than 30,000 ICU patients (including more than 700 patients with COVID-19) from two academic medical centers. The performance of the model with a 24-h prediction horizon at the development and validation sites was comparable (AUC, 0.895 vs 0.882, respectively), providing significant improvement over traditional clinical criteria (P < .001). Prospective validation of the algorithm among patients with COVID-19 yielded AUCs in the range of 0.918 to 0.943., Interpretation: A transparent deep learning algorithm improves on traditional clinical criteria to predict the need for MV in hospitalized patients, including in those with COVID-19. Such an algorithm may help clinicians to optimize timing of tracheal intubation, to allocate resources and staff better, and to improve patient care., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)