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• Debate around schools re-opening during the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic in Italy remains strong. • A rapid-antigen-test-based screening campaign was conducted. • An extremely low number of cases of SARS-CoV-2 were identified. • A school re-opening strategy, with preventive measures in place, should be considered. In the coronavirus disease 2019 era, debate around the risk of contagion in school is intense in Italy. The Department of Welfare and Health of Florence promoted a screening campaign with rapid antigen tests for all students and school personnel. The aim of this study was to assess the circulation of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in the school setting by means of mass screening in every primary and middle school in Florence. All students and school personnel at primary and middle schools in Florence were asked to take part. The campaign started on 16 November 2020 and was completed on 12 February 2021. If a subject had a positive result on rapid antigen testing, a molecular test was performed to confirm the result. In total, 18,414 subjects were tested: 15,233 students (82.7%) and 3181 school personnel (17.3%). The rapid antigen test gave a positive result in 27 cases (0.15%). Of these, only 14 tests were confirmed to be positive on molecular testing. These results show a very low number of cases of SARS-CoV-2 among the study subjects (0.08%). These results show that the spread of SARS-CoV-2 in the school setting was low in Florence during the screening period. [ABSTRACT FROM AUTHOR]