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Background: Screening programs that pre-emptively and routinely test population groups for disease at a massive scale were first implemented during the COVID-19 pandemic in a handful of countries. One of these countries was Greece, which implemented a mass self-testing program during 2021. In contrast to most other non-pharmaceutical interventions (NPIs), mass self-testing programs are particularly attractive for their relatively small financial and social burden, and it is therefore important to understand their effectiveness to inform policy makers and public health officials responding to future pandemics. This study aimed to estimate the number of deaths and hospitalizations averted by the program implemented in Greece and evaluate the impact of several operational decisions., Methods: Granular data from the mass self-testing program deployed by the Greek government between April and December 2021 were obtained. The data were used to fit a novel compartmental model that was developed to describe the dynamics of the COVID-19 pandemic in Greece in the presence of self-testing. The fitted model provided estimates on the effectiveness of the program in averting deaths and hospitalizations. Sensitivity analyses were used to evaluate the impact of operational decisions, including the scale of the program, targeting of sub-populations, and sensitivity (i.e., true positive rate) of tests., Results: Conservative estimates show that the program reduced the reproduction number by 4%, hospitalizations by 25%, and deaths by 20%, translating into approximately 20,000 averted hospitalizations and 2,000 averted deaths in Greece between April and December 2021., Conclusion: Mass self-testing programs are efficient NPIs with minimal social and financial burden; therefore, they are invaluable tools to be considered in pandemic preparedness and response., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Gilmour, Sapounas, Drakopoulos, Jaillet, Magiorkinis and Trichakis.)