Background: The world has been confronted with the COVID-19 pandemic for more than one year. Severe disease is more often found among elderly people, whereas most young children and adolescents show mild symptoms or even remain asymptomatic, so that infection might be undiagnosed. Therefore, only limited epidemiological data on SARS-CoV-2 infection in children and young adults are available., Objective: This study aims to determine the prevalence of SARS-CoV-2 antibodies in children from the city of Tübingen, Germany, and to measure the incidence of new cases over 12 months., Methods: SARS-CoV-2 antibodies will be measured in saliva as a surrogate for a previous SARS-CoV-2 infection. Children will be sampled at their preschools, primary schools, and secondary schools at three time points: July 2020, October to December 2020, and April to July 2021. An adult cohort will be sampled at the same time points (ie, adult comparator group). The saliva-based SARS-CoV-2-antibody enzyme-linked immunosorbent assay will be validated using blood and saliva samples from adults with confirmed previous SARS-CoV-2 infections (ie, adult validation group)., Results: The first study participant was enrolled in July 2020, and recruitment and enrollment continued until July 2021. We have recruited and enrolled 1850 children, 560 adults for the comparator group, and 83 adults for the validation group. We have collected samples from the children and the adults for the comparator group at the three time points. We followed up with participants in the adult validation group every 2 months and, as of the writing of this paper, we were at time point 7. We will conduct data analysis after the data collection period., Conclusions: Infection rates in children are commonly underreported due to a lack of polymerase chain reaction testing. This study will report on the prevalence of SARS-CoV-2 infections in infants, school children, and adolescents as well as the incidence change over 12 months in the city of Tübingen, Germany. The saliva sampling approach for SARS-CoV-2-antibody measurement allows for a unique, representative, population-based sample collection process., Trial Registration: ClinicalTrials.gov NCT04581889; https://clinicaltrials.gov/ct2/show/NCT04581889., International Registered Report Identifier (irrid): DERR1-10.2196/27739., (©Yudi T Pinilla, Evelyn Friessinger, Johanna Marie Griesbaum, Lilith Berner, Constanze Heinzel, Käthe Elsner, Rolf Fendel, Jana Held, Andrea Kreidenweiss. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 08.10.2021.)