Introduction: Health Care Workers (HCWs) are at a particular high risk of SARS-CoV-2 infection due to direct and indirect exposure to COVID-19 patients and Aerosol-Generating Procedures (AGPs). The aim of the study was to assess the risk factors for SARS-CoV-2 infection in HCWs exposed to COVID-19 patients, to evaluate the adherence and effectiveness of Infection Prevention and Control (IPC) measures, to describe the clinical presentation for SARS-CoV-2 infection in HCWs and to determine serological responses in HCWs. Methods: HCWs exposed to COVID-19 patients during the previous 14 days with a confirmed case status were recruited as cases; HCWs exposed to COVID-19 patients during the previous 14 days in the same ward without a suspected/probable/confirmed case status were recruited as controls. Serum samples were collected as soon as possible and after 21–28 days from all participants. Data were collected with a WHO standardized questionnaire as soon as possible and after 21–28 days. Results: All social, occupational and personal variables considered were not associated with an increased risk of SARS-CoV-2 infection. Conclusions: Our study showed a high knowledge of IPC measures and very high PPE use among HCWs.