During the SARS-CoV-2 pandemic, reliable scientific data was of paramount importance—worldwide, in Germany, and in Rhineland-Palatinate. The interdisciplinary Gutenberg COVID-19 Study (GCS) made a significant contribution in this regard: With 10,250 participants, it was one of the largest population-based studies conducted during the pandemic. It collected comprehensive data in the Mainz-Bingen area for the first time and investigated the epidemiology of SARS-CoV-2 in Rhineland-Palatinate. In addition to the direct consequences of SARS-CoV-2 infection, the study also comprehensively analyzed the health impacts of the pandemic and the measures taken to contain it. The study was funded by the European Regional Development Fund (ERDF/REACT-EU), the Rhineland-Palatinate Ministry of Science and Health, the ReALity Initiative for Life Sciences at Johannes Gutenberg University Mainz, and the National Research Network of University Hospitals (NUM).