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<h4>Objectives</h4>Accurate and reliable criteria to rapidly estimate the probability of infection with the novel coronavirus-2 that causes the severe acute respiratory syndrome (SARS-CoV-2) and associated disease (COVID-19) remain an urgent unmet need, especially in emergency care. The objective was to derive and validate a clinical prediction score for SARS-CoV-2 infection that uses simple criteria widely available at the point of care.<h4>Methods</h4>Data came from the registry data from the national REgistry of suspected COVID-19 in EmeRgency care (RECOVER network) comprising 116 hospitals from 25 states in the US. Clinical variables and 30-day outcomes were abstracted from medical records of 19,850 emergency department (ED) patients tested for SARS-CoV-2. The criterion standard for diagnosis of SARS-CoV-2 required a positive molecular test from a swabbed sample or positive antibody testing within 30 days. The prediction score was derived from a 50% random sample (n = 9,925) using unadjusted analysis of 107 candidate variables as a screening step, followed by stepwise forward logistic regression on 72 variables.<h4>Results</h4>Multivariable regression yielded a 13-variable score, which was simplified to a 13-point score: +1 point each for age>50 years, measured temperature>37.5°C, oxygen saturation<95%, Black race, Hispanic or Latino ethnicity, household contact with known or suspected COVID-19, patient reported history of dry cough, anosmia/dysgeusia, myalgias or fever; and -1 point each for White race, no direct contact with infected person, or smoking. In the validation sample (n = 9,975), the probability from logistic regression score produced an area under the receiver operating characteristic curve of 0.80 (95% CI: 0.79-0.81), and this level of accuracy was retained across patients enrolled from the early spring to summer of 2020. In the simplified score, a score of zero produced a sensitivity of 95.6% (94.8-96.3%), specificity of 20.0% (19.0-21.0%), negative likelihood ratio of 0.22 (0.19-0.26). Increasing points on the simplified score predicted higher probability of infection (e.g., >75% probability with +5 or more points).<h4>Conclusion</h4>Criteria that are available at the point of care can accurately predict the probability of SARS-CoV-2 infection. These criteria could assist with decisions about isolation and testing at high throughput checkpoints.