Funding Information: Open Access funding enabled and organized by Projekt DEAL. This research received the contribution of the EuCARE Project funded by the European Union´s Horizon Europe Research and Innovation Programme under Grant Agreement No 101046016. The study is funded by the European Union and the study proposal has undergone a competitive peer review process. Role of the funder: the EU has launched a call for projects to which the study proposal answered. The call defined the general themes of research for the applying projects. The EU periodically carries out reviews on the advancement status of the study and quality assessment of its deliverables. The EU does not interfere with the scientific decisions and conduct of the study nor in the analysis of the results. The funding is administered to the participant centres by the study coordinator EuResist Network GEIE. This work was partially supported by the Italian Ministry of Health with Ricerca Corrente and 5X1000 funds. The funding bodies played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. Funding Information: Eucare WP4: Maria Chiara Mommo, Michael Böhm, Michal Rosen-Zvi, Yishai Shimoni, Sivan Ravid, Tal Kozlovski, Sofia Seabra, Victor Pimentel, Mafalda Miranda, Dora Vaz, Giuseppina Tucci, Juan Manuel Baez, Carmen Romero, Francesco Vairo, Martina Spaziante, Valeria Gabellone, Giulia Vaglio, Fabrizio Fedele. We would like to thank school personnel, students and parents for participating in the EuCARE study. Participating schools up to now are the following: Scuola Maria Ausiliatrice (Lodi), Liceo Scientifico G. Gandini (Lodi), Scuola Infanzia Pio XII (Lodi), Fondazione Scuola materna (Rivolta D'Adda), Istituto Tecnico Industriale Statale Enrico Mattei (San Donato), Liceo Leonardo da Vinci (Casalecchio di Reno), I.C. Ammirato Falcone (Lecce), Direzione didattica statale 5° circolo “Livio Tempesta” (Lecce), I.C 1° Polo “S. Colonna”(Monteroni di Lecce), I.C. E. De Amicis (Squinzano), I.C. Magistrato Giovanni Falcone (Copertino), I.C. Castro dei Volsci, Agrupamento de Escolas Dr. Azevedo Neves (Amadora, Portugal). Funding Information: The EuCARE consortium involves 18 partners from 10 different countries and has been funded by the European Commission in the frame of the research aimed at fighting SARS-CoV2 virus and its variants, in the context of the EuCARE project, “European Cohorts of Patients and Schools to Advance Response to Epidemics”. The project’s ultimate goal is to find solutions to safely support school reopening within the COVID-19 pandemic on the basis of scientific evidence, taking in consideration the impact that a prolonged school closure can have on education, wellbeing and personal development of children. Publisher Copyright: © 2022, The Author(s). Background: Contradictory results were reported on the role of school closure/reopening on the overall SARS-CoV-2 transmission rate, as well as on which kind and level of mitigation measures implemented in schools may be effective in limiting its diffusion. Some recent studies were reassuring, showing that opening did not increase the community spread, although teachers and families are worried about the high class density. On the other hand, distance learning was associated with a negative impact on learning, sociability and psychological health, especially in vulnerable children. As it becomes clear that the SARS-CoV-2 pandemic will last for a long time, there is a high need for studies and solutions to support safe schools opening based on scientific evidence of harms and benefits. The Lolli-Methode (LM) is a strategy for epidemiological surveillance and early intervention aiming at SARS-CoV-2 outbreaks’ reduction in schools, relying on polymerase chain reaction analysis of saliva samples. Methods: In this cluster randomised trial protocol, we aim to determine whether the LM is useful to support schools opening and to reduce clusters and attack rates in schools, compared with the standard of care (SoC) surveillance by public health departments. This multicenter study will enrol 440 classes (around 8800 students, teachers and other personnel) from two countries, cluster randomised to LM or SoC. The samples from the pools will be collected and tested using PCR-based techniques. Test results will be combined with questionnaires filled in by children, parents, schoolteachers, and principals, concerning ongoing mitigation measures, their perceived psychological impact and other health and socio-economic information. An ancillary observational study will be carried out to study the prevalence of SARS-CoV-2 in schools, frequencies and size of clusters and attack rates, to compare the effectiveness of the different preventive measures adopted and to evaluate psychological issues in students and teachers in relation to the pandemic’s containment measures. Discussion: By the end of this study, we will have defined and characterised the applicability of the LM for SARS-CoV-2 surveillance, as well as the impact of pandemic preventive measures on children and teachers. Trial registration International Standard Randomised Controlled Trial Number: NCT05396040, 27.05.2022. publishersversion published