question: IntroductionHealthcare workers (HCW) working through the pandemic are in the front line for infection, psychological pressure and overwork.ObjectivesTo identify modifiable work factors associated with COVID-19 infection and mental distress, and to assess the effectiveness of provisions to mitigate their impact.MethodsA cohort study of HCWs was set up in the first weeks of the pandemic in Canada. HCWs from British Columbia, Alberta, Ontario, and Quebec completed an online questionnaire in the spring/summer of 2020, and a Phase 2 questionnaire from October 2020. They also provided a blood sample to assess SARS-CoV-2 antibodies. HCWs reporting a COVID-19 infection after the Phase 2 questionnaire were matched on job-type and province to 4 referents for a nested case-referent (C-R) study concentrating on exposures immediately prior to infection. Phase 3 is underway, with a final contact planned for March 2022.Results5135 HCWs completed the Phase 1 questionnaire with 93% (4539/4857) of those eligible completing Phase 2. By March 1st 2021, 157 cases had been confirmed by PCR and a further 10 found positive only on antibody testing (an overall rate of 3.3%). The odds of infection doubled for working one-on-one with known COVID-19 patients. Rates were lower in physicians and nurses, compared to personal support workers, health care aides, and licensed practical nurses. HCWs in a hospital setting had lower rates than those working in the community, where shortages of personal protective equipment were more widespread. High rates of anxiety (on the Hospital Anxiety and Depression Scale) were recorded in both Phase 1 and 2. Only 1 in 4 HCW had used available mental health supports. By May 2021, 100 cases with 389 referents had been recruited to the on-going C-R study.ConclusionInformation collected prospectively has the potential to improve HCWs protection during this and future epidemics.