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Background: The Emergency Department (ED) is directly involved in diagnosis and initial treatment of all stages of COVID-19. One major goal of the ED is to decide, whether patients need to be hospitalized or can be sent home safely. These decisions must usually be made without knowing the SARS-CoV-2 test result. Methods: We retrieved all patients who were treated at the ED of the Charite (Berlin, Germany) during the pandemic peak between March 1 and April 15, 2020 and who underwent SARS-CoV-2 testing using an oro-naso-pharyngeal swab. All patients with positive test results were characterized in detail and underwent a follow-up in hospital or outpatient setting after at least 7 days via telehealth. Logistic regression and classification and regression tree (CART) analyses were performed to identify predictors, which either justify hospital admission or confirm safe discharge. The results were validated using an independent second multiple-center cohort collated from data of four other university EDs from the ReCoVer registry. The clinical endpoint was all cause mortality or need for mechanical ventilation during index stay or after re-admission. Results: The primary test population of suspected COVID-19 consisted of n=1,255 cases, 45.2% were female (n=567). Of these, n=110 tested positive for SARS-CoV-2 (8.8%). The median age of SARS-CoV-2 positive cases was 45 years (IQR: 33-66 years), whereas the median age of the group tested negative for SARS-CoV-2 was 42 years (IQR: 30-60 years) (p=0.096). 43.6% were directly admitted to hospital care (n=48). The factors, which were significantly associated with hospitalization in univariate analysis were oxygen saturation (< 95%), age, dyspnea, time since onset of symptoms, history of cardiovascular (CV) disease, lactate, LDH and C-reactive protein (CRP). CART analysis identified the variables oxygen saturation (< 95%), dyspnea and history of cardiovascular (CV) disease were of particular importance to distinguish between high and low risk groups. If all three variables were negative, most patients were discharged from ED, and the incidence of the clinical endpoint was 0%. Vice versa if the criteria were present, the incidence of the clinical endpoint was 7.7% in patients with dyspnea only and 10.0% in patients with either CV-disease or O2-satuaration below 95%. The validation cohort confirmed the safety of discharge (1 event) and revealed an incidence of the clinical endpoint in different risk categories from 14.3% in patients with CV-disease only, 9.4% in patients with dyspnea and 18.2% in patients with O2-satuaration below 95%. Conclusions: Based on easily available variables like dyspnea, oxygen saturation, history of CV disease, approximately 25% of patients subsequently confirmed with COVID-19 can be identified for safe discharge. Further prospective studies are needed to identify more patients, who can be treated out of hospital. Funding Statement: There was no third party funding for this research. Declaration of Interests: The authors declare no conflicts of interest related to this work. Ethics Approval Statement: The Ethics Committee of the Charite – Universitatsmedizin Berlin approved the project as a sub-study of an influenza study. (EA2/204/19).