Healthcare workers were at a high risk of infection early in the SARS-CoV-2 pandemic. It is uncertain to what extent occupational, household and community factors contributed, and how this changed over time. We aimed to characterise the risk factors for infection over four successive waves of the pandemic in a large, UK healthcare worker cohort (SIREN).

Participants underwent fortnightly SARS-CoV-2 PCR testing and symptom/exposure questionnaire. Attack rates and adjusted OR of infection were calculated according to participant characteristics and exposures for each wave between 1st October 2020 and 30th August 2022.

19,427 participants were included in the second wave, 20,260 in the third, 11,937 in the fourth, and 6503 in the fifth. The attack rates of infection were 9.1% (alpha), 6.6% (delta), 36.6% (omicron BA.1/2) and 15.9% (omicron BA.4/5), respectively.

Occupational risk factors were only apparent in the second wave, during which significant social distancing measures were in place. These were identified as working as a healthcare assistant, nurse or bedside therapist, and working on an inpatient ward. Occupational exposure requiring personal protective equipment was also a risk.

In subsequent waves, without social restrictions, occupational characteristics were not risk factors. Instead, living with others compared to living alone was a risk, particularly children. During the third wave (winter 2021–2022), having a colleague with COVID-19 was identified as a risk for the first time.

Our findings highlight clinical areas and occupational groups in which there may be scope to prevent healthcare-associated infections, particularly during winter pressures. Prospective studies targeting these are essential to establish which interventions are most effective. This study also underscores the importance of community circulation and exposures when considering healthcare workforce protection.