Abstract Objectives This longitudinal cohort study aims to assess the extent and patterns of seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in school-attending children, and their parents and school personnel. It will examine risk factors for infection, the relationship between seropositivity and symptoms, and temporal persistence of antibodies. Methods The study (Ciao Corona) will enroll a regionally representative, random sample of schools in the canton of Zurich, where 18% of the Swiss population live. Children aged 5–16 years, attending primary and secondary schools, and their parents and school personnel are invited. Venous blood and saliva samples are collected for serological testing in June/July 2020, in October/November 2020, and in March/April 2021. Bi-monthly questionnaires will cover SARS-CoV-2 symptoms and tests, health, preventive behavior, and lifestyle information. Hierarchical Bayesian logistic regression models will account for sensitivity and specificity of the serological tests in the analyses and complex sampling structure, i.e., clustering within classes and schools. Results and conclusions This unique school-based study will allow describing temporal trends of immunity, evaluate effects of preventive measures and will inform goal-oriented policy decisions during subsequent outbreaks. Trial registration ClinicalTrials.gov Identifier: NCT04448717, registered June 26, 2020. https://clinicaltrials.gov/ct2/show/NCT04448717.