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Background: Asymptomatic and paucisymptomatic infections account for a substantial portion of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) transmissions. The value of intensified screening strategies, especially in emergency departments (EDs), in reaching asymptomatic and paucisymptomatic patients and helping to improve detection and reduce transmission has not been documented. The objective of this study was to evaluate in EDs whether an intensified SARS-CoV-2 screening strategy combining nurse-driven screening for asymptomatic/paucisymptomatic patients with routine practice (intervention) could contribute to higher detection of SARS-CoV-2 infections compared to routine practice alone, including screening for symptomatic or hospitalized patients (control). Methods and findings: We conducted a cluster-randomized, two-period, crossover trial from February 2021 to June 2021 in 18 EDs in the Paris metropolitan area, France. All adults visiting the EDs were eligible. At the start of the first period, 18 EDs were randomized to the intervention or control strategy by balanced block randomization with stratification, with the alternative condition being applied in the second period. During the control period, routine screening for SARS-CoV-2 included screening for symptomatic or hospitalized patients. During the intervention period, in addition to routine screening practice, a questionnaire about risk exposure and symptoms and a SARS-CoV-2 screening test were offered by nurses to all remaining asymptomatic/paucisymptomatic patients. The primary outcome was the proportion of newly diagnosed SARS-CoV-2–positive patients among all adults visiting the 18 EDs. Primary analysis was by intention-to-treat. The primary outcome was analyzed using a generalized linear mixed model (Poisson distribution) with the center and center by period as random effects and the strategy (intervention versus control) and period (modeled as a weekly categorical variable) as fixed effects with additional adjustment for community incidence. During the intervention and control periods, 69,248 patients and 69,104 patients, respectively, were included for a total of 138,352 patients. Patients had a median age of 45.0 years [31.0, 63.0], and women represented 45.7% of the patients. During the intervention period, 6,332 asymptomatic/paucisymptomatic patients completed the questionnaire; 4,283 were screened for SARS-CoV-2 by nurses, leading to 224 new SARS-CoV-2 diagnoses. A total of 1,859 patients versus 2,084 patients were newly diagnosed during the intervention and control periods, respectively (adjusted analysis: 26.7/1,000 versus 26.2/1,000, adjusted relative risk: 1.02 (95% confidence interval (CI) [0.94, 1.11]; p = 0.634)). The main limitation of this study is that it was conducted in a rapidly evolving epidemiological context. Conclusions: The results of this study showed that intensified screening for SARS-CoV-2 in EDs was unlikely to identify a higher proportion of newly diagnosed patients. Trial registration: Trial registration number: ClinicalTrials.gov NCT04756609. Judith Leblanc and co-workers report a cluster-randomized trial evaluating intensive screening for SARS-CoV-2 infection in emergency departments. Author summary: Why was this study done?: Undetected asymptomatic Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infections or paucisymptomatic infections with mild symptoms are responsible for a substantial portion of transmissions, which has been a major challenge in managing the Coronavirus Disease 2019 (COVID-19) pandemic. Free and widely available screening has been offered in many countries to reach asymptomatic/paucisymptomatic infectious individuals and improve detection, reduce transmission, and help contain the pandemic. To our knowledge, the value of systematically offering screening during medical consultations, particularly in emergency departments (EDs), to identify asymptomatic/paucisymptomatic infectious individuals has not been evaluated. What did the researchers do and find?: The objective of this trial was to evaluate whether an intensified screening strategy involving screening for asymptomatic/paucisymptomatic patients and routine screening of symptomatic and hospitalized patients (intervention) could lead to a higher proportion of new diagnoses compared with routine screening (control) in 18 EDs in the Paris metropolitan region. During the intervention period, 4,283 asymptomatic/paucisymptomatic patients were screened, leading to 224 new diagnoses. Overall, 1,859 patients were newly diagnosed during the intervention period versus 2,084 during the control period, corresponding, after analysis, to 26.7 new diagnoses/1,000 patients versus 26.2/1,000. The proportion of new diagnoses among asymptomatic/paucisymptomatic patients in EDs was higher than that in community screenings in the region. Comparison with findings from a mathematical model indicated that ED data allowed the estimation of regional incidences for asymptomatic/paucisymptomatic infections. What do these findings mean?: The results of this study showed that the intensified screening strategy was unlikely to bring a substantial benefit to the detection of SARS-CoV-2 infections. The population screened in EDs appeared to be more affected by SARS-CoV-2 than the general population screened in the region. Intensified screening in EDs could allow access to individuals who are less likely to be reached by the general screening system. The main limitation of this study is that it was conducted in a changing epidemiological context, which encourages further exploration of screening strategies for asymptomatically transmitted respiratory viruses to better define the observatory role of EDs in emerging epidemics. [ABSTRACT FROM AUTHOR]