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Background: This study explored the extent of COVID-19 vaccination coverage and investigated drivers and barriers to COVID-19 vaccine uptake among people in prison. Methods: This cross-sectional study was conducted from July to October 2021 among 517 detained people in the Campania region of South Italy. Results: In total, 47.1% of participants expressed a high concern about contracting COVID-19 after vaccination, whereas 60.6% and 53.8% of respondents reported a positive attitude towards usefulness and safety of COVID-19 vaccines, respectively. Adherence to the active offer of COVID-19 vaccination involved 89.7% of detained subjects. COVID-19 vaccination uptake was significantly higher in females, and in those who reported influenza vaccination uptake, had received information about COVID-19 vaccination from media and newspapers, did not express need of additional information about COVID-19 vaccine, believed that COVID-19 vaccine is safe, were involved in working activities in the prison, and had a high school or university degree. Conclusions: These findings showed a high self-reported COVID-19 vaccination coverage in detained subjects, supporting the effectiveness of the strategy aimed at giving priority to COVID-19 vaccinations in prisons. Further efforts are needed to contrast the hesitancy of those who refused vaccination to increase their confidence about usefulness and safety of COVID-19 vaccines.