•We evaluated the performance of the Sofia SARS-CoV-2 rapid antigen test (Ag-RDT)•A total of 7877 patients were included in a prospective and monocentric study•Overall sensitivity of Ag-RDT compared to RT-PCR was 62.9% and specificity 99.4%•In a subset of symptomatic and RT-PCR positive patients sensitivity was 72.1%•The Ag-RDT proved to be a rapid tool to detect patients with high viral loads (Ct-value ≤25) The rapid and reliable detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is of high importance for individual patient care and hospital infection prevention. We aimed to evaluate the performance of the Sofia SARS-CoV-2 antigen rapid diagnostic test (Ag-RDT) in comparison to real-time reverse-transcription polymerase chain reaction (RT-PCR). We conducted a prospective, monocentric cross-sectional study in an emergency department of a German university hospital from November 2020 to March 2021. We tested all samples using both Sofia SARS-CoV-2 Ag-RDT and real-time RT-PCR. A total of 7877 patients were included. Overall sensitivity of the Ag-RDT was 62.9% and specificity was 99.4%. Sensitivity varied across study months, whereas specificity remained high. Sensitivity increased to 94.2% in samples with a cycle threshold (Ct)-value ≤25. The Sofia Ag-RDT proved to be a rapid tool to detect samples with high viral loads (Ct-value ≤25) and might thus help to identify infectious patients.