Healthcare workers (HCWs) have increased exposure and subsequent risk of infection with SARS-CoV-2. This case-control study was conducted to investigate the contemporaneous risks associated with confirmed SARS-CoV-2 infection amongst HCWs following in-work exposure to a confirmed COVID-19 case. We assessed the influence of demographic (age, sex, nationality, high risk co-morbidities and vaccination status) and work-related factors (job role, exposure location, contact type, PPE use) on infection risk following nosocomial SARS-CoV-2 exposure. All contact tracing records within the hospital site during Waves 1-3 of the COVID-19 pandemic in Ireland were screened to identify exposure events, cases and controls. 285 cases and 1526 controls were enrolled, as a result of 1811 in-work exposure events with 745 index cases. We demonstrate that male sex, Eastern European nationality, exposure location, PPE use and vaccination status all impact the likelihood of SARS-CoV-2 infection following nosocomial SARS-CoV-2 exposure. The findings draw attention to the need for continuing emphasis on PPE use and its persisting benefit in the era of COVID-19 vaccinations. We suggest that non-work-related factors may influence infection risk seen in certain ethnic groups and that infection risk in high-risk HCW roles (e.g. nursing) may be the result of repeated exposures rather than risks inherent to a single event.