OBJECTIVES: To compare the Lumipulse® SARS-CoV-2 antigen test with the gold standard real-time reverse transcription-polymerase chain reaction (RT-PCR) for diagnosis of SARS-CoV-2 infection and to evaluate its role in screening programs. METHODS: Lumipulse® SARS-CoV-2 antigen assay was compared with the gold standard RT-PCR test in a selected cohort of 226 subjects with suspected SARS-CoV-2 infection, and its accuracy was evaluated. Subsequently, the test was administered to a real-life screening cohort of 1738 cases. ROC analysis was performed to explore test features and cutoffs. All tests were performed in the regional reference laboratory in Umbria, Italy. RESULTS: A 42.0% positive result at RT-PCR was observed in the selected cohort. The Lumipulse® system showed 92.6% sensitivity (95% CI 85.4-97.0%) and 90.8% specificity (95% CI 84.5-95.2%) at 1.24 pg/mL optimal cutoff. In the screening cohort, characterized by 5.2% prevalence of infection, Lumipulse® assay showed 100% sensitivity (95% CI 96.0-100.0%) and 94.8% specificity (95% CI 93.6-95.8%) at 1.645 pg/mL optimal cutoff; the AUC was 97.4%, NPV was 100% (95% CI 99.8-100.0%) and PPV was 51.1% (95% CI 43.5-58.7%). CONCLUSIONS: The Lumipulse® SARS-CoV-2 antigen assay can be safely employed in the screening strategies in small and large communities and in the general population.