ObjectiveWe aimed to measure the prevalence of psychological distress among Quebec healthcare workers (HCWs) during the second and third pandemic waves and to assess the effect of psychosocial risk factors (PSRs) on work-related psychological distress among SARS-CoV-2 infected (cases) and non-infected (controls) HCWs.MethodsA self-administered survey was used to measure validated indicators of psychological distress (K6 scale) and PSR (questions based on Karasek and Siegrist models, value conflicts and work-life balance). Adjusted robust Poisson models were used to estimate prevalence ratios.Results4068 cases and 4152 controls completed the survey. Prevalence of high work-related psychological distress was 42%; it was associated with PSRs (mainly work-life balance, value conflicts and high psychological demands) but not with SARS-CoV-2 infection.ConclusionPrimary prevention measures targeting PSRs are needed to reduce mental health risks of HCWs.