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Abstract Objective: Current guidance states that asymptomatic screening for severe acute respiratory coronavirus virus 2 (SARS-CoV-2) prior to admission to an acute-care setting is at the facility’s discretion. This study’s objective was to estimate the number of undetected cases of SARS-CoV-2 admitted as inpatients under 4 testing approaches and varying assumptions. Design and setting: Individual-based microsimulation of 104 North Carolina acute-care hospitals Patients: All simulated inpatient admissions to acute-care hospitals from December 15, 2021, to January 13, 2022 [ie, during the SARS-COV-2 ο (omicron) variant surge]. Interventions: We simulated (1) only testing symptomatic patients, (2) 1-stage antigen testing with no confirmatory polymerase chain reaction (PCR) test, (3) 1-stage antigen testing with a confirmatory PCR for negative results, and (4) serial antigen screening (ie, repeat antigen test 2 days after a negative result). Results: Over 1 month, there were 77,980 admissions: 13.7% for COVID-19, 4.3% with but not for COVID-19, and 82.0% for non–COVID-19 indications without current infection. Without asymptomatic screening, 1,089 (credible interval [CI], 946–1,253) total SARS-CoV-2 infections (7.72%) went undetected. With 1-stage antigen screening, 734 (CI, 638–845) asymptomatic infections (67.4%) were detected, with 1,277 false positives. With combined antigen and PCR screening, 1,007 (CI, 875–1,159) asymptomatic infections (92.5%) were detected, with 5,578 false positives. A serial antigen testing policy detected 973 (CI, 845–1,120) asymptomatic infections (89.4%), with 2,529 false positives. Conclusions: Serial antigen testing identified >85% of asymptomatic infections and resulted in fewer false positives with less cost per identified infection compared to combined antigen plus PCR testing.